sGC STIMULATORS

ABSTRACT

Compounds of Formula IA and Formula IB are described. They are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds may be useful for treating, preventing or managing various disorders that are herein disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation application of U.S. patentapplication Ser. No. 13/833,910, filed Dec. 12, 2013, now allowed. U.S.patent application Ser. No. 13/833,910 which is a National Phaseapplication of international application number PCT/2011/058902, filedon Nov. 2, 2011, which claims the benefits of priority of U.S.Provisional Application Nos. 61/411,730 filed Nov. 9, 2010 and61/546,707 filed Oct. 13, 2011. The disclosures of all priorapplications are hereby incorporated by reference herein in theirentirety.

FIELD OF THE INVENTION

The present disclosure relates to stimulators of soluble guanylatecyclase (sGC), pharmaceutical formulations thereof and methods of usingthe stimulators, alone or in combination with one or more additionalagents, for treating and/or preventing various diseases, wherein anincrease in the concentration of nitric oxide (NO) might be desirable.

BACKGROUND OF THE INVENTION

Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide(NO) in vivo. sGC can be activated via both NO-dependent andNO-independent mechanisms. In response to this activation, sGC convertsGTP into the secondary messenger cyclic GMP (cGMP). The increased levelof cGMP, in turn, modulates the activity of downstream effectorsincluding protein kinases, phosphodiesterases (PDEs), and ion channels.

In the body, NO is synthesized from arginine and oxygen by variousnitric oxide synthase (NOS) enzymes and by sequential reduction ofinorganic nitrate. Three distinct isoforms of NOS have been identified:inducible NOS (iNOS or NOS II) found in activated macrophage cells;constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmissionand long term potentiation; and constitutive endothelial NOS (eNOS orNOS III) which regulates smooth muscle relaxation and blood pressure.

Experimental and clinical evidence indicates that reducedbioavailability and/or responsiveness to endogenously produced NOcontributes to the development of cardiovascular, endothelial, renal andhepatic disease, as well as erectile dysfunction. In particular, the NOsignaling pathway is altered in cardiovascular diseases, including, forinstance, systemic and pulmonary hypertension, heart failure, stroke,thrombosis and atherosclerosis.

Pulmonary hypertension (PH) is a disease characterized by sustainedelevation of blood pressure in the pulmonary vasculature (pulmonaryartery, pulmonary vein and pulmonary capillaries), which results inright heart hypertrophy, eventually leading to right heart failure anddeath. In PH, the bioactivity of NO and other vasodilators such asprostacyclin is reduced, whereas the production of endogenousvasoconstrictors such as endothelin is increased, resulting in excessivepulmonary vasoconstriction. sGC stimulators have been used to treat PHbecause they promote smooth muscle relaxation, which leads tovasodilation.

Treatment with NO-independent sGC stimulators also promoted smoothmuscle relaxation in the corpus cavernosum of healthy rabbits, rats andhumans, causing penile erection, indicating that sGC stimulators areuseful for treating erectile dysfunction.

NO-independent, heme-dependent, sGC stimulators, such as those disclosedherein, have several important differentiating characteristics,including crucial dependency on the presence of the reduced prostheticheme moiety for their activity, strong synergistic enzyme activationwhen combined with NO and stimulation of the synthesis of cGMP by directstimulation of sGC, independent of NO. The benzylindazole compound YC-1was the first sGC stimulator to be identified. Additional sGCstimulators with improved potency and specificity for sGC have sincebeen developed. These compounds have been shown to produceanti-aggregatory, anti-proliferative and vasodilatory effects.

Since compounds that stimulate sGC in an NO-independent manner offerconsiderable advantages over other current alternative therapies, thereis a need to develop novel stimulators of sGC. They would be useful inthe prevention, management and treatment of disorders such as pulmonaryhypertension, arterial hypertension, heart failure, atherosclerosis,inflammation, thrombosis, renal fibrosis and failure, liver cirrhosis,erectile dysfunction and other cardiovascular disorders.

SUMMARY OF THE INVENTION

The present invention is directed to compounds according to Formula IAor IB, or a pharmaceutically acceptable salt thereof,

wherein:

-   the symbol of the encircled letter B represents ring B, and ring B    is a phenyl or a 6-membered heteroaryl ring, containing 1 or 2    nitrogen ring atoms;-   n is an integer selected from 0 to 3;-   each J^(B) is independently selected from halogen, —CN, —NO₂, a C₁₋₆    aliphatic, —OR^(B) or a C₃₋₈ cycloaliphatic group; wherein each said    C₁₋₆ aliphatic and each said C₃₋₈ cycloaliphatic group is optionally    and independently substituted with up to 3 instances of R³;-   each R^(B) is independently selected from hydrogen, a C₁₋₆ aliphatic    or a C₃₋₈ cycloaliphatic; wherein each said C₁₋₆ aliphatic and each    said C₃₋₈ cycloaliphatic ring is optionally and independently    substituted with up to 3 instances of R³;-   each R³ is independently selected from halogen, —CN, C₁₋₄ alkyl,    C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl);-   X is selected from N or C;-   each Y is independently selected from C, N, O or S;-   m is an integer selected from 0 to 3;-   each J^(D) is a substituent on a carbon or nitrogen ring atom and is    independently selected from halogen, —NO₂, —OR^(D), —SRS,    —C(O)R^(D), —C(O)OR^(D), —C(O)N(R^(D))₂, —CN, —N(R^(D))₂,    —N(R^(d))C(O)R^(D), —N(Rd)C(O)OR^(D), —SO₂R^(D), —SO₂N(RD)₂,    —N(Rd)SO₂R^(D), a C₁₋₆ aliphatic, —(C₁₋₆ aliphatic)-R^(D), a C₃₋₈    cycloaliphatic ring, a 6 to 10-membered aryl ring, a 4 to 8-membered    heterocyclic ring or a 5 to 10-membered heteroaryl ring; wherein    each said 4 to 8-membered heterocylic ring and each said 5 to    10-membered heteroaryl ring contains between 1 and 3 heteroatoms    independently selected from O, N or S; and wherein each said C₁₋₆    aliphatic, each said C₃₋₈ cycloaliphatic ring, each said 6 to    10-membered aryl ring, each said 4 to 8-membered heterocyclic ring    and each said 5 to 10-membered heteroaryl ring is optionally and    independently substituted with up to 3 instances of R⁵;-   each R^(D) is independently selected from hydrogen, a C₁₋₆    aliphatic, —(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4    to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered    heteroaryl ring; wherein each said 4 to 8-membered heterocylic ring    and each said 5 to 6-membered heteroaryl ring contains between 1 and    3 heteroatoms independently selected from O, N or S; and wherein    each said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring, each    said 4 to 8-membered heterocyclic ring, each said phenyl and each    said 5 to 6-membered heteroaryl ring is optionally and independently    substituted with up to 3 instances of R⁵;-   each R^(d) is independently selected from hydrogen, a C₁₋₆    aliphatic, —(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4    to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered    heteroaryl ring; wherein each said heterocylic ring and each said    heteroaryl ring contains between 1 and 3 heteroatoms independently    selected from O, N or S; and wherein each said C₁₋₆ aliphatic, each    said C₃₋₈ cycloaliphatic ring, each said 4 to 8-membered    heterocyclic ring, each said phenyl and each said 5 to 6-membered    heteroaryl ring is optionally and independently substituted by up to    3 instances of R⁵;-   each R^(f) is independently selected from a C₃₋₈ cycloaliphatic    ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 to    6-membered heteroaryl ring; wherein each said heterocylic ring and    each said heteroaryl ring contains between 1 and 3 heteroatoms    independently selected from O, N or S; and wherein each said C₁₋₆    aliphatic, each said C₃₋₈ cycloaliphatic ring, each said 4 to    8-membered heterocyclic ring, each said phenyl and each said 5 to    6-membered heteroaryl ring is optionally and independently    substituted by up to 3 instances of R⁵;-   alternatively, two instances of R^(D) linked to the same nitrogen    atom of J^(D), together with said nitrogen atom of J^(D), form a 4    to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;    wherein each said 4 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring optionally contains up to 2 additional    heteroatoms independently selected from N, O or S, and wherein each    said 4 to 8-membered heterocyclic ring and each said 5-membered    heteroaryl ring is optionally and independently substituted by up to    3 instances of R⁵; or-   alternatively, one instance of R^(D) linked to a carbon, oxygen or    sulfur atom of J^(D) and one instance of R^(d) linked to a nitrogen    atom of the same J^(D), together with said carbon, oxygen or sulfur    and said nitrogen atom of that same J^(D), form a 4 to 8-membered    heterocyclic ring or a 5-membered heteroaryl ring; wherein each said    4 to 8-membered heterocyclic ring and each said 5-membered    heteroaryl ring optionally contains up to 2 additional heteroatoms    independently selected from N, O or S, and wherein each said 4 to    8-membered heterocyclic ring and each said 5-membered heteroaryl    ring is optionally and independently substituted by up to 3    instances of R⁵;-   each R⁵ is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄    cyanoalkyl, —OR⁶, —SR⁶, —CORE, —C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁶)C(O)R⁶,    —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an oxo group;    wherein each said phenyl group is optionally and independently    substituted with up to 3 instances of halogen, —OH, —NH₂, —NH(C₁₋₄    alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,    —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and wherein each said C₇₋₁₂    aralkyl and each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R⁶ is independently selected from hydrogen, a C₁₋₄ alkyl,    phenyl, a C₇₋₁₂ aralkyl or a C₃₋₈ cycloalkyl ring; wherein each of    said C₁₋₄ alkyl, each said phenyl, each said C₇₋₁₂ aralkyl and each    said cycloalkyl group is optionally and independently substituted    with up to 3 instances of halogen;-   alternatively, two instances of R⁶ linked to the same nitrogen atom    of R⁵, together with said nitrogen atom of R⁵, form a 5 to    8-membered heterocyclic ring or a 5-membered heteroaryl ring;    wherein each said 5 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring optionally contains up to 2 additional    heteroatoms independently selected from N, O or S; or-   alternatively, one instance of R⁶ linked to a nitrogen atom of R⁵    and one instance of R⁶ linked to a carbon or sulfur atom of the same    R⁵, together with said nitrogen and said carbon or sulfur atom of    the same R⁵, form a 5 to 8-membered heterocyclic ring or a    5-membered heteroaryl ring; wherein each said 5 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring    optionally contains up to 2 additional heteroatoms independently    selected from N, O or S;-   or, alternatively, two J^(D) groups attached to two vicinal ring D    atoms, taken together with said two vicinal ring D atoms, form a 5    to 7-membered heterocycle resulting in a fused ring D wherein said 5    to 7-membered heterocycle contains from 1 to 3 heteroatoms    independently selected from N, O or S; and wherein said 5 to    7-membered heterocycle is optionally and independently substituted    by up to 3 instances of halogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄    alkyl)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl), —O(C₁₋₄    haloalkyl) or oxo;-   R^(C) is selected a halogen, —CN, C₁₋₆ alkyl or a ring C;-   ring C is a phenyl ring, a monocyclic 5 or 6-membered heteroaryl    ring, a bicyclic 8 to 10-membered heteroaryl ring, a monocyclic 3 to    10-membered cycloaliphatic ring, or a monocyclic 4 to 10-membered    heterocycle; wherein said monocyclic 5 or 6-membered heteroaryl    ring, said bicyclic 8 to 10-membered heteroaryl ring, or said    monocyclic 4 to 10-membered heterocycle contain between 1 and 4    heteroatoms selected from N, O or S; and wherein said phenyl,    monocyclic 5 to 6-membered heteroaryl ring, bicyclic 8 to    10-membered heteroaryl ring, or monocyclic 4 to 10-membered    heterocycle is optionally and independently substituted with up to 3    instances of J^(C);-   each J^(C) is independently selected from halogen, —CN, —NO₂, a C₁₋₆    aliphatic, —OR^(H), —SR^(H), —N(R^(H))₂, a C₃₋₈ cycloaliphatic ring    or a 4 to 8-membered heterocyclic ring; wherein said 4 to 8-membered    heterocyclic ring contains 1 or 2 heteroatoms independently selected    from N, O or S; wherein each said C₁₋₆ aliphatic, each said C₃₋₈    cycloaliphatic ring and each said 4 to 8-membered heterocyclic ring,    is optionally and independently substituted with up to 3 instances    of R⁷; or alternatively, two J^(C) groups attached to two vicinal    ring C atoms, taken together with said two vicinal ring C atoms,    form a 5 to 7-membered heterocycle resulting in a fused ring C;    wherein said 5 to 7-membered heterocycle contains from 1 to 2    heteroatoms independently selected from N, O or S;-   each R^(H) is independently selected from hydrogen, a C₁₋₆    aliphatic, a C₃₋₈ cycloaliphatic ring or a 4 to 8-membered    heterocyclic ring; wherein each said 4 to 8-membered heterocylic    ring contains between 1 and 3 heteroatoms independently selected    from O, N or S; and wherein each said C₁₋₆ aliphatic, each said C₃₋₈    cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring, is    optionally and independently substituted with up to 3 instances of    R⁷;-   alternatively, two instances of R^(H) linked to the same nitrogen    atom of r, together with said nitrogen atom of r, form a 4 to    8-membered heterocyclic ring or a 5-membered heteroaryl ring;    wherein each said 4 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring optionally contains up to 2 additional    heteroatoms independently selected from N, O or S, and wherein each    said 4 to 8-membered heterocyclic ring and each said 5-membered    heteroaryl ring is optionally and independently substituted by up to    3 instances of R⁷; or-   each R⁷ is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring, —01V, —SR⁸, —N(R⁸)₂, or    an oxo group; wherein each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R⁸ is independently selected from hydrogen, a C₁₋₄ alkyl, C₁₋₄    haloalkyl or a C₃₋₈ cycloalkyl ring; wherein each said cycloalkyl    group is optionally and independently substituted with up to 3    instances of halogen;-   alternatively, two instances of R⁸ linked to the same nitrogen atom    of R⁷, together with said nitrogen atom of R⁷, form a 5 to    8-membered heterocyclic ring or a 5-membered heteroaryl ring;    wherein each said 5 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring optionally contains up to 2 additional    heteroatoms independently selected from N, O or S;-   R^(A) is selected from hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄    haloalkyl; provided that the compound is not one of the compounds    represented below:

The invention also provides pharmaceutical compositions comprising acompound of Formula IA or Formula IB or a pharmaceutically acceptablesalt thereof.

The invention also provides a method of treating or preventing adisease, health condition or disorder in a subject in need thereof,comprising administering, alone or in combination therapy, atherapeutically or prophylactically effective amount of the compound ofFormula IA or Formula IB or a pharmaceutically acceptable salt thereofto the subject; wherein the disease, health condition or disorder is aperipheral or cardiac vascular disorder/condition, or a urogenitalsystem disorder that can benefit from sGC stimulation.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulae. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments.Rather, the invention is intended to cover all alternatives,modifications and equivalents that may be included within the scope ofthe present invention as defined by the claims. The present invention isnot limited to the methods and materials described herein but includeany methods and materials similar or equivalent to those describedherein that could be used in the practice of the present invention. Inthe event that one or more of the incorporated literature references,patents or similar materials differ from or contradict this application,including but not limited to defined terms, term usage, describedtechniques or the like, this application controls.

DEFINITIONS AND GENERAL TERMINOLOGY

For purposes of this disclosure, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version, and theHandbook of Chemistry and Physics, 75^(th) Ed. 1994. Additionally,general principles of organic chemistry are described in “OrganicChemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999,and “March's Advanced Organic Chemistry”, 5^(th) Ed., Smith, M. B. andMarch, J., eds. John Wiley & Sons, New York: 2001, which are hereinincorporated by reference in their entirety.

As described herein, compounds of Formula IA or Formula IB may beoptionally substituted with one or more substituents, such asillustrated generally below, or as exemplified by particular classes,subclasses, and species of the invention. The phrase “optionallysubstituted” is used interchangeably with the phrase “substituted orunsubstituted.” In general, the term “substituted”, refers to thereplacement of one or more hydrogen radicals in a given structure withthe radical of a specified substituent. Unless otherwise indicated, anoptionally substituted group may have a substituent at eachsubstitutable position of the group. When more than one position in agiven structure can be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at each position. If a substituent radical or structure isnot identified or defined as “optionally substituted”, the substituentradical or structure is not substituted. As will be apparent to one ofordinary skill in the art, groups such as —H, halogen, —NO₂, —CN, —OH,—NH₂ or —OCF₃ would not be substitutable groups.

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, or 3. As described herein, aspecified number range of atoms includes any integer therein. Forexample, a group having from 1-4 atoms could have 1, 2, 3 or 4 atoms.When any variable occurs more than one time at any position, itsdefinition on each occurrence is independent from every otheroccurrence.

Selection of substituents and combinations envisioned by this disclosureare only those that result in the formation of stable or chemicallyfeasible compounds. Such choices and combinations will be apparent tothose of ordinary skill in the art and may be determined without undueexperimentation. The term “stable”, as used herein, refers to compoundsthat are not substantially altered when subjected to conditions to allowfor their production, detection, and, in some embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 25° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

A compound, such as the compounds of Formula IA or Formula IB or othercompounds herein disclosed, may be present in its free form or as partof a co-form. The compound may be present in a solid form (e.g. anamorphous form, or a crystalline form or polymorph). Under certainconditions, compounds may also form salts. When one of the components inthe co-form has clearly transferred a proton to the other component, theresulting co-form is referred to as a “salt”. The formation of a salt isdetermined by how large the difference is in the pKas between thepartners that form the mixture.

Unless only one of the isomers is drawn or named specifically,structures depicted herein are also meant to include all stereoisomeric(e.g., enantiomeric, diastereomeric, atropoisomeric and cis-transisomeric) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Ra and Sa configurations foreach asymmetric axis, (Z) and (E) double bond configurations, and cisand trans conformational isomers. Therefore, single stereochemicalisomers as well as racemates, and mixtures of enantiomers,diastereomers, and cis-trans isomers (double bond or conformational) ofthe present compounds are within the scope of the present disclosure.Unless otherwise stated, all tautomeric forms of the compounds of thepresent disclosure are within the scope of the disclosure.

The present disclosure also embraces isotopically-labeled compoundswhich are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. All isotopes of any particular atom or element as specified arecontemplated within the scope of the compounds of the invention, andtheir uses. Exemplary isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C,¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and¹²⁵I, respectively. Certain isotopically-labeled compounds of thepresent invention (e.g., those labeled with ³H and ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (i.e.,³H) and carbon-14 (i.e., ¹⁴C) isotopes are useful for their ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present invention can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein below, by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms. In other embodiments, aliphatic groups contain 1-4aliphatic carbon atoms and in yet other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms. Suitable aliphatic groups include,but are not limited to, linear or branched, substituted or unsubstitutedalkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groupsinclude, but are not limited to: methyl, ethyl, propyl, butyl,isopropyl, isobutyl, vinyl, sec-butyl, tert-butyl, butenyl, propargyl,acetylene and the like.

The term “alkyl”, as used herein, refers to a saturated linear orbranched-chain monovalent hydrocarbon radical. Unless otherwisespecified, an alkyl group contains 1-20 carbon atoms (e.g., 1-20 carbonatoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbonatoms or 1-3 carbon atoms). Examples of alkyl groups include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.

The term “alkenyl” refers to a linear or branched-chain monovalenthydrocarbon radical with at least one site of unsaturation, i.e., acarbon-carbon, sp² double bond, wherein the alkenyl radical includesradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations. Unless otherwise specified, an alkenyl groupcontains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms,2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbonatoms). Examples include, but are not limited to, vinyl, allyl and thelike.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical with at least one site of unsaturation, i.e., a carbon-carbon sptriple bond. Unless otherwise specified, an alkynyl group contains 2-20carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbonatoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). Examplesinclude, but are not limited to, ethynyl, propynyl, and the like.

The term “carbocyclic” refers to a ring system formed only by carbon andhydrogen atoms. Unless otherwise specified, throughout this disclosure,carbocycle is used as a synonym of “non-aromatic carbocycle” or“cycloaliphatic”. In some instances the term can be used in the phrase“aromatic carbocycle”, and in this case it refers to an “aryl group” asdefined below.

The term “cycloaliphatic” (or “non-aromatic carbocycle”, “non-aromaticcarbocyclyl”, “non-aromatic carbocyclic”) refers to a cyclic hydrocarbonthat is completely saturated or that contains one or more units ofunsaturation but which is not aromatic, and which has a single point ofattachment to the rest of the molecule. Unless otherwise specified, acycloaliphatic group may be monocyclic, bicyclic, tricyclic, fused,spiro or bridged. In one embodiment, the term “cycloaliphatic” refers toa monocyclic C₃-C₁₂ hydrocarbon or a bicyclic C₇-C₁₂ hydrocarbon. Insome embodiments, any individual ring in a bicyclic or tricyclic ringsystem has 3-7 members. Suitable cycloaliphatic groups include, but arenot limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples ofaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl,norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl,cyclododecyl, and the like.

The term “cycloaliphatic” also includes polycyclic ring systems in whichthe non-aromatic carbocyclic ring can be “fused” to one or more aromaticor non-aromatic carbocyclic or heterocyclic rings or combinationsthereof, as long as the radical or point of attachment is on thenon-aromatic carbocyclic ring.

“Heterocycle” (or “heterocyclyl” or “heterocyclic), as used herein,refers to a ring system in which one or more ring members are anindependently selected heteroatom, which is completely saturated or thatcontains one or more units of unsaturation but which is not aromatic,and which has a single point of attachment to the rest of the molecule.Unless otherwise specified, through this disclosure, heterocycle is usedas a synonym of “non-aromatic heterocycle”. In some instances the termcan be used in the phrase “aromatic heterocycle”, and in this case itrefers to a “heteroaryl group” as defined below. The term heterocyclealso includes fused, spiro or bridged heterocyclic ring systems. Unlessotherwise specified, a heterocycle may be monocyclic, bicyclic ortricyclic. In some embodiments, the heterocycle has 3-18 ring members inwhich one or more ring members is a heteroatom independently selectedfrom oxygen, sulfur or nitrogen, and each ring in the system contains 3to 7 ring members. In other embodiments, a heterocycle may be amonocycle having 3-7 ring members (2-6 carbon atoms and 1-4 heteroatoms)or a bicycle having 7-10 ring members (4-9 carbon atoms and 1-6heteroatoms). Examples of bicyclic heterocyclic ring systems include,but are not limited to: adamantanyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl.

As used herein, the term “heterocycle” also includes polycyclic ringsystems wherein the heterocyclic ring is fused with one or more aromaticor non-aromatic carbocyclic or heterocyclic rings, or with combinationsthereof, as long as the radical or point of attachment is on theheterocyclic ring.

Examples of heterocyclic rings include, but are not limited to, thefollowing monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino,3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the followingbicycles: 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

As used herein, the term “aryl” (as in “aryl ring” or “aryl group”),used alone or as part of a larger moiety, as in “aralkyl”, “aralkoxy”,“aryloxyalkyl”, refers to a carbocyclic ring system wherein at least onering in the system is aromatic and has a single point of attachment tothe rest of the molecule. Unless otherwise specified, an aryl group maybe monocyclic, bicyclic or tricyclic and contain 6-18 ring members. Theterm also includes polycyclic ring systems where the aryl ring is fusedwith one or more aromatic or non-aromatic carbocyclic or heterocyclicrings, or with combinations thereof, as long as the radical or point ofattachment is in the aryl ring. Examples of aryl rings include, but arenot limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluorenyl,and anthracenyl.

The term “aralkyl” refers to a radical having an aryl ring substitutedwith an alkylene group, wherein the open end of the alkylene groupallows the aralkyl radical to bond to another part of the compound ofFormula IA or Formula IB. The alkylene group is a bivalent,straight-chain or branched, saturated hydrocarbon group. As used herein,the term “C₇₋₁₂ aralkyl” means an aralkyl radical wherein the totalnumber of carbon atoms in the aryl ring and the alkylene group combinedis 7 to 12. Examples of “aralkyl” include, but not limited to, a phenylring substituted by a C₁₋₆ alkylene group, e.g., benzyl and phenylethyl,and a naphthyl group substituted by a C₁₋₂ alkylene group.

The term “heteroaryl” (or “heteroaromatic” or “heteroaryl group” or“aromatic heterocycle”) used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy” refers to a ring system wherein atleast one ring in the system is aromatic and contains one or moreheteroatoms, wherein each ring in the system contains 3 to 7 ringmembers and which has a single point of attachment to the rest of themolecule. Unless otherwise specified, a heteroaryl ring system may bemonocyclic, bicyclic or tricyclic and have a total of five to fourteenring members. In one embodiment, all rings in a heteroaryl system arearomatic. Also included in this definition are heteroaryl radicals wherethe heteroaryl ring is fused with one or more aromatic or non-aromaticcarbocyclic or heterocyclic rings, or combinations thereof, as long asthe radical or point of attachment is in the heteroaryl ring. Bicyclic6, 5 heteroaromatic system, as used herein, for example, is a sixmembered heteroaromatic ring fused to a second five membered ringwherein the radical or point of attachment is on the six-membered ring.

Heteroaryl rings include, but are not limited to the followingmonocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl,4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl(e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl(e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, andthe following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl,benzopyrazinyl, benzopyranonyl, indolyl (e.g., 2-indolyl), purinyl,quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), andisoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or4-isoquinolinyl).

As used herein, “cyclo” (or “cyclic”, or “cyclic moiety”) encompassesmono-, bi- and tri-cyclic ring systems including cycloaliphatic,heterocyclic, aryl or heteroaryl, each of which has been previouslydefined.

“Fused” bicyclic ring systems comprise two rings which share twoadjoining ring atoms.

“Bridged” bicyclic ring systems comprise two rings which share three orfour adjacent ring atoms. As used herein, the term “bridge” refers to anatom or a chain of atoms connecting two different parts of a molecule.The two atoms that are connected through the bridge (usually but notalways, two tertiary carbon atoms) are referred to as “bridgeheads”. Inaddition to the bridge, the two bridgeheads are connected by at leasttwo of individual atoms or chains of atoms. Examples of bridged bicyclicring systems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. “Spiro” bicyclic ring systems shareonly one ring atom (usually a quaternary carbon atom) between the tworings.

The term “ring atom” refers to an atom such as C, N, O or S that is partof the ring of an aromatic group, a cycloaliphatic group or a heteroarylring. A “substitutable ring atom” is a ring carbon or nitrogen atombonded to at least one hydrogen atom. The hydrogen can be optionallyreplaced with a suitable substituent group. Thus, the term“substitutable ring atom” does not include ring nitrogen or carbon atomswhich are shared when two rings are fused. In addition, “substitutablering atom” does not include ring carbon or nitrogen atoms when thestructure depicts that they are already attached to one or more moietyother than hydrogen and no hydrogens are available for substitution.

“Heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon, including any oxidized form of nitrogen, sulfur,phosphorus, or silicon, the quaternized form of any basic nitrogen, or asubstitutable nitrogen of a heterocyclic or heteroaryl ring, for exampleN (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

In some embodiments, two independent occurrences of a variable may betaken together with the atom(s) to which each variable is bound to forma 5-8-membered, heterocyclyl, aryl, or heteroaryl ring or a 3-8-memberedcycloalkyl ring. Exemplary rings that are formed when two independentoccurrences of a substituent are taken together with the atom(s) towhich each variable is bound include, but are not limited to thefollowing: a) two independent occurrences of a substituent that arebound to the same atom and are taken together with that atom to form aring, where both occurrences of the substituent are taken together withthe atom to which they are bound to form a heterocyclyl, heteroaryl,carbocyclyl or aryl ring, wherein the group is attached to the rest ofthe molecule by a single point of attachment; and b) two independentoccurrences of a substituent that are bound to different atoms and aretaken together with both of those atoms to form a heterocyclyl,heteroaryl, carbocyclyl or aryl ring, wherein the ring that is formedhas two points of attachment with the rest of the molecule. For example,where a phenyl group is substituted with two occurrences of R^(o) as inFormula D1:

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring as in Formula D2:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of a substituent are taken together with theatom(s) to which each substituent is bound and that the examplesdetailed above are not intended to be limiting.

In some embodiments, an alkyl or aliphatic chain can be optionallyinterrupted with another atom or group. This means that a methylene unitof the alkyl or aliphatic chain can optionally be replaced with saidother atom or group. Unless otherwise specified, the optionalreplacements form a chemically stable compound. Optional interruptionscan occur both within the chain and/or at either end of the chain; i.e.both at the point of attachment(s) to the rest of the molecule and/or atthe terminal end. Two optional replacements can also be adjacent to eachother within a chain so long as it results in a chemically stablecompound. Unless otherwise specified, if the replacement or interruptionoccurs at a terminal end of the chain, the replacement atom is bound toan H on the terminal end. For example, if —CH₂CH₂CH₃ were optionallyinterrupted with —O—, the resulting compound could be —OCH₂CH₃,—CH₂OCH₃, or —CH₂CH₂OH. In another example, if the divalent linker—CH₂CH₂CH₂— were optionally interrupted with —O—, the resulting compoundcould be —OCH₂CH₂—, —CH₂OCH₂—, or —CH₂CH₂O—. The optional replacementscan also completely replace all of the carbon atoms in a chain. Forexample, a C₃ aliphatic can be optionally replaced by —N(R′)—, —C(O)—,and —N(R′)— to form —N(R′)C(O)N(R′)— (a urea).

In general, the term “vicinal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a groupwithin a substituent. A group is terminal when the group is present atthe end of the substituent not further bonded to the rest of thechemical structure. Carboxyalkyl, i.e., R^(X)O)C-alkyl is an example ofa carboxy group used terminally. A group is internal when the group ispresent in the middle of a substituent at the end of the substituentbound to the rest of the chemical structure. Alkylcarboxy (e.g.,alkyl-C(O)O— or alkyl-O(CO)—) and alkylcarboxyaryl (e.g.,alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groupsused internally.

As described herein, a bond drawn from a substituent to the center ofone ring within a multiple-ring system (as shown below), representssubstitution of the substituent at any substitutable position in any ofthe rings within the multiple ring system. For example, formula D3represents possible substitution in any of the positions shown informula D4:

This also applies to multiple ring systems fused to optional ringsystems (which would be represented by dotted lines). For example, inFormula D5, X is an optional substituent both for ring A and ring B.

If, however, two rings in a multiple ring system each have differentsubstituents drawn from the center of each ring, then, unless otherwisespecified, each substituent only represents substitution on the ring towhich it is attached. For example, in Formula D6, Y is an optionalsubstituent for ring A only, and X is an optional substituent for ring Bonly.

As used herein, the terms “alkoxy” or “alkylthio” refer to an alkylgroup, as previously defined, attached to the molecule, or to anotherchain or ring, through an oxygen (“alkoxy” i.e., —O-alkyl) or a sulfur(“alkylthio” i.e., —S-alkyl) atom.

The terms C_(n-m) “alkoxyalkyl”, C_(n-m) “alkoxyalkenyl”, C_(n-m)“alkoxyaliphatic”, and C_(n-m) “alkoxyalkoxy” mean alkyl, alkenyl,aliphatic or alkoxy, as the case may be, substituted with one or morealkoxy groups, wherein the combined total number of carbons of the alkyland alkoxy groups, alkenyl and alkoxy groups, aliphatic and alkoxygroups or alkoxy and alkoxy groups, combined, as the case may be, isbetween the values of n and m. For example, a C₄₋₆ alkoxyalkyl has atotal of 4-6 carbons divided between the alkyl and alkoxy portion; e.g.it can be —CH₂OCH₂CH₂CH₃, —CH₂CH₂OCH₂CH₃ or —CH₂CH₂CH₂OCH₃.

When the moieties described in the preceding paragraph are optionallysubstituted, they can be substituted in either or both of the portionson either side of the oxygen or sulfur. For example, an optionallysubstituted C₄ alkoxyalkyl could be, for instance, —CH₂CH₂OCH₂(Me)CH₃ or—CH₂(OH)O CH₂CH₂CH₃; a C₅ alkoxyalkenyl could be, for instance, —CH═CHOCH₂CH₂CH₃ or —CH═CHCH₂OCH₂CH₃.

The terms aryloxy, arylthio, benzyloxy or benzylthio, refer to an arylor benzyl group attached to the molecule, or to another chain or ring,through an oxygen (“aryloxy”, benzyloxy e.g., —O-Ph, —OCH₂Ph) or sulfur(“arylthio” e.g., —S-Ph, —S—CH₂Ph) atom. Further, the terms“aryloxyalkyl”, “benzyloxyalkyl” “aryloxyalkenyl” and “aryloxyaliphatic”mean alkyl, alkenyl or aliphatic, as the case may be, substituted withone or more aryloxy or benzyloxy groups, as the case may be. In thiscase, the number of atoms for each aryl, aryloxy, alkyl, alkenyl oraliphatic will be indicated separately. Thus, a 5-6-memberedaryloxy(C₁₋₄ alkyl) is a 5-6 membered aryl ring, attached via an oxygenatom to a C₁₋₄ alkyl chain which, in turn, is attached to the rest ofthe molecule via the terminal carbon of the C₁₋₄ alkyl chain.

As used herein, the terms “halogen” or “halo” mean F, Cl, Br, or I.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be,substituted with one or more halogen atoms. For example a C₁₋₃ haloalkylcould be —CFHCH₂CHF₂ and a C₁₋₂ haloalkoxy could be —OC(Br)HCHF₂. Thisterm includes perfluorinated alkyl groups, such as —CF₃ and —CF₂CF₃.

As used herein, the term “cyano” refers to —CN or —C≡N.

The terms “cyanoalkyl”, “cyanoalkenyl”, “cyanoaliphatic”, and“cyanoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more cyano groups. For example a C₁₋₃cyanoalkyl could be —C(CN)₂CH₂CH₃ and a C₁₋₂ cyanoalkenyl could be═CHC(CN)H₂.

As used herein, an “amino” group refers to —NH₂.

The terms “aminoalkyl”, “aminoalkenyl”, “aminoaliphatic”, and“aminoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more amino groups. For example a C₁₋₃aminoalkyl could be —CH(NH₂)CH₂CH₂NH₂ and a C₁₋₂ aminoalkoxy could be—OCH₂CH₂NH₂.

The term “hydroxyl” or “hydroxy” refers to —OH.

The terms “hydroxyalkyl”, “hydroxyalkenyl”, “hydroxyaliphatic”, and“hydroxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the casemay be, substituted with one or more —OH groups. For example a C₁₋₃hydroxyalkyl could be —CH₂(CH₂OH)CH₃ and a C₄ hydroxyalkoxy could be—OCH₂C(CH₃)(OH)CH₃.

As used herein, a “carbonyl”, used alone or in connection with anothergroup refers to —C(O)— or —C(O)H. For example, as used herein, an“alkoxycarbonyl,” refers to a group such as —C(O)O(alkyl).

As used herein, an “oxo” refers to ═O, wherein oxo is usually, but notalways, attached to a carbon atom (e.g., it can also be attached to asulfur atom). An aliphatic chain can be optionally interrupted by acarbonyl group or can optionally be substituted by an oxo group, andboth expressions refer to the same: e.g. —CH₂—C(O)—CH₃.

As used herein, in the context of resin chemistry (e.g. using solidresins or soluble resins or beads), the term “linker” refers to abifunctional chemical moiety attaching a compound to a solid support orsoluble support.

In all other situations, a “linker”, as used herein, refers to adivalent group in which the two free valences are on different atoms(e.g. carbon or heteroatom) or are on the same atom but can besubstituted by two different substituents. For example, a methylenegroup can be C₁ alkyl linker (—CH₂—) which can be substituted by twodifferent groups, one for each of the free valences (e.g. as inPh-CH₂-Ph, wherein methylene acts as a linker between two phenyl rings).Ethylene can be C₂ alkyl linker (—CH₂CH₂—) wherein the two free valencesare on different atoms. The amide group, for example, can act as alinker when placed in an internal position of a chain (e.g. —CONH—). Alinker can be the result of interrupting an aliphatic chain by certainfunctional groups or of replacing methylene units on said chain by saidfunctional groups. E.g. a linker can be a C₁₋₆ aliphatic chain in whichup to two methylene units are substituted by —C(O)— or —NH—(as in—CH₂—NH—CH₂—C(O)—CH₂— or —CH₂—NH—C(O)—CH₂—). An alternative way todefine the same —CH₂—NH—CH₂—C(O)—CH₂— and —CH₂—NH—C(O)—CH₂— groups is asa C₃ alkyl chain optionally interrupted by up to two —C(O)— or —NH—moieties. Cyclic groups can also form linkers: e.g. a1,6-cyclohexanediyl can be a linker between two R groups, as in

A linker can additionally be optionally substituted in any portion orposition.

Divalent groups of the type R—CH═ or R₂C═, wherein both free valencesare in the same atom and are attached to the same substituent, are alsopossible. In this case, they will be referred to by their IUPAC acceptednames. For instance an alkylidene (such as, for example, a methylidene(═CH₂) or an ethylidene (═CH—CH₃)) would not be encompassed by thedefinition of a linker in this disclosure.

The term “protecting group”, as used herein, refers to an agent used totemporarily block one or more desired reactive sites in amultifunctional compound. In certain embodiments, a protecting group hasone or more, or preferably all, of the following characteristics: a)reacts selectively in good yield to give a protected substrate that isstable to the reactions occurring at one or more of the other reactivesites; and b) is selectively removable in good yield by reagents that donot attack the regenerated functional group. Exemplary protecting groupsare detailed in Greene, T. W. et al., “Protective Groups in OrganicSynthesis”, Third Edition, John Wiley & Sons, New York: 1999, the entirecontents of which is hereby incorporated by reference. The term“nitrogen protecting group”, as used herein, refers to an agents used totemporarily block one or more desired nitrogen reactive sites in amultifunctional compound. Preferred nitrogen protecting groups alsopossess the characteristics exemplified above, and certain exemplarynitrogen protecting groups are detailed in Chapter 7 in Greene, T. W.,Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition,John Wiley & Sons, New York: 1999, the entire contents of which arehereby incorporated by reference.

As used herein, the term “displaceable moiety” or “leaving group” refersto a group that is associated with an aliphatic or aromatic group asdefined herein and is subject to being displaced by nucleophilic attackby a nucleophile.

As used herein, “amide coupling agent” or “amide coupling reagent” meansa compound that reacts with the hydroxyl moiety of a carboxy moietythereby rendering it susceptible to nucleophilic attack. Exemplary amidecoupling agents include DIC (diisopropylcarbodiimide), EDCI(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC(dicyclohexylcarbodiimide), BOP(benzotriazol-1-yloxy-tris(dimethylamino)-phosphoniumhexafluorophosphate), pyBOP((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate),etc.

One of the aspects of the present invention is directed to a compoundaccording to Formula IA or IB, or a pharmaceutically acceptable saltthereof,

wherein:

the symbol with the encircled letter B represents ring B, and ring B isa phenyl or a 6-membered heteroaryl ring, containing 1 or 2 nitrogenring atoms;

n is an integer selected from 0 to 3;

each J^(B) is independently selected from halogen, —CN, —NO₂, a C₁₋₆aliphatic, —OR^(B) or a C₃₋₈ cycloaliphatic group; wherein each saidC₁₋₆ aliphatic and each said C₃₋₈ cycloaliphatic group is optionally andindependently substituted with up to 3 instances of R³;

each RB is independently selected from hydrogen, a C₁₋₆ aliphatic or aC₃₋₈ cycloaliphatic; wherein each said C₁₋₆ aliphatic and each said C₃₋₈cycloaliphatic ring is optionally and independently substituted with upto 3 instances of R³;

each R³ is independently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl);

X is selected from N or C;

each Y is independently selected from C, N, O or S;

m is an integer selected from 0 to 3;

each J^(D) is a substituent on a carbon or nitrogen ring atom and isindependently selected from halogen, —NO₂, —OR^(D), —SRS, —C(O)R^(D),—C(O)ORS, —C(O)N(RD)₂, —CN, —N(R^(D))₂, —N(R^(d))C(O)R^(D),—N(Rd)C(O)OR^(D), —SO₂R^(D), —SO₂N(R^(D))₂, —N(R^(d))SO₂R^(D), a C₁₋₆aliphatic, —(C₁₋₆ aliphatic)-R^(D), a C₃₋₈ cycloaliphatic ring, a 6 to10-membered aryl ring, a 4 to 8-membered heterocyclic ring or a 5 to10-membered heteroaryl ring; wherein each said 4 to 8-memberedheterocylic ring and each said 5 to 10-membered heteroaryl ring containsbetween 1 and 3 heteroatoms independently selected from O, N or S; andwherein each said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring,each said 6 to 10-membered aryl ring, each said 4 to 8-memberedheterocyclic ring and each said 5 to 10-membered heteroaryl ring isoptionally and independently substituted with up to 3 instances of R⁵;

each R^(D) is independently selected from hydrogen, a C₁₋₆ aliphatic,—(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4 to 8-memberedheterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; whereineach said 4 to 8-membered heterocylic ring and each said 5 to 6-memberedheteroaryl ring contains between 1 and 3 heteroatoms independentlyselected from O, N or S; and wherein each said C₁₋₆ aliphatic, each saidC₃₋₈ cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,each said phenyl and each said 5 to 6-membered heteroaryl ring isoptionally and independently substituted with up to 3 instances of R⁵;

each R^(d) is independently selected from hydrogen, a C₁₋₆ aliphatic,—(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4 to 8-memberedheterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; whereineach said heterocylic ring and each said heteroaryl ring containsbetween 1 and 3 heteroatoms independently selected from O, N or S; andwherein each said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring,each said 4 to 8-membered heterocyclic ring, each said phenyl and eachsaid 5 to 6-membered heteroaryl ring is optionally and independentlysubstituted by up to 3 instances of R⁵;

each R^(f) is independently selected from a C₃₋₈ cycloaliphatic ring, a4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-memberedheteroaryl ring; wherein each said heterocylic ring and each saidheteroaryl ring contains between 1 and 3 heteroatoms independentlyselected from O, N or S; and wherein each said C₁₋₆ aliphatic, each saidC₃₋₈ cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,each said phenyl and each said 5 to 6-membered heteroaryl ring isoptionally and independently substituted by up to 3 instances of R⁵;

alternatively, two instances of R^(D) linked to the same nitrogen atomof J^(D), together with said nitrogen atom of J^(D), form a 4 to8-membered heterocyclic ring or a 5-membered heteroaryl ring; whereineach said 4 to 8-membered heterocyclic ring and each said 5-memberedheteroaryl ring optionally contains up to 2 additional heteroatomsindependently selected from N, O or S, and wherein each said 4 to8-membered heterocyclic ring and each said 5-membered heteroaryl ring isoptionally and independently substituted by up to 3 instances of R⁵; or

alternatively, one instance of R^(D) linked to a carbon, oxygen orsulfur atom of J^(D) and one instance of R^(d) linked to a nitrogen atomof the same J^(D), together with said carbon, oxygen or sulfur and saidnitrogen atom of that same J^(D), form a 4 to 8-membered heterocyclicring or a 5-membered heteroaryl ring; wherein each said 4 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring optionallycontains up to 2 additional heteroatoms independently selected from N, Oor S, and wherein each said 4 to 8-membered heterocyclic ring and eachsaid 5-membered heteroaryl ring is optionally and independentlysubstituted by up to 3 instances of R⁵;

each R⁵ is independently selected from halogen, —CN, —NO₂, C₁₋₄ alkyl, aC₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl,—OR⁶, —SR⁶, —CORE, —C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶,—SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an oxo group; wherein each saidphenyl group is optionally and independently substituted with up to 3instances of halogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂,—CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl);and wherein each said C₇₋₁₂ aralkyl and each said cycloalkyl group isoptionally and independently substituted with up to 3 instances ofhalogen;

each R⁶ is independently selected from hydrogen, a C₁₋₄ alkyl, phenyl, aC₇₋₁₂ aralkyl or a C₃₋₈ cycloalkyl ring; wherein each of said C₁₋₄alkyl, each said phenyl, each said C₇₋₁₂ aralkyl and each saidcycloalkyl group is optionally and independently substituted with up to3 instances of halogen;

alternatively, two instances of R⁶ linked to the same nitrogen atom ofR⁵, together with said nitrogen atom of R⁵, form a 5 to 8-memberedheterocyclic ring or a 5-membered heteroaryl ring; wherein each said 5to 8-membered heterocyclic ring and each said 5-membered heteroaryl ringoptionally contains up to 2 additional heteroatoms independentlyselected from N, O or S; or

alternatively, one instance of R⁶ linked to a nitrogen atom of R⁵ andone instance of R⁶ linked to a carbon or sulfur atom of the same R⁵,together with said nitrogen and said carbon or sulfur atom of the sameR⁵, form a 5 to 8-membered heterocyclic ring or a 5-membered heteroarylring; wherein each said 5 to 8-membered heterocyclic ring and each said5-membered heteroaryl ring optionally contains up to 2 additionalheteroatoms independently selected from N, O or S;

or, alternatively, two J^(D) groups attached to two vicinal ring Datoms, taken together with said two vicinal ring D atoms, form a 5 to7-membered heterocycle resulting in a fused ring D wherein said 5 to7-membered heterocycle contains from 1 to 3 heteroatoms independentlyselected from N, O or S; and wherein said 5 to 7-membered heterocycle isoptionally and independently substituted by up to 3 instances ofhalogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo;

R^(C) is selected from halo, —CN, C₁₋₆ alkyl or a ring C;

ring C is a phenyl ring, a monocyclic 5 or 6-membered heteroaryl ring, abicyclic 8 to 10-membered heteroaryl ring, a monocyclic 3 to 10-memberedcycloaliphatic ring, or a monocyclic 4 to 10-membered heterocycle;wherein said monocyclic 5 or 6-membered heteroaryl ring, said bicyclic 8to 10-membered heteroaryl ring, or said monocyclic 4 to 10-memberedheterocycle contain between 1 and 4 heteroatoms selected from N, O or S;and wherein said phenyl, monocyclic 5 to 6-membered heteroaryl ring,bicyclic 8 to 10-membered heteroaryl ring, or monocyclic 4 to10-membered heterocycle is optionally and independently substituted withup to 3 instances of J^(C);

each J^(C) is independently selected from halogen, —CN, —NO₂, a C₁₋₆aliphatic, —OR^(H), —SR^(H), —N(R^(H))₂, a C₃₋₈ cycloaliphatic ring or a4 to 8-membered heterocyclic ring; wherein said 4 to 8-memberedheterocyclic ring contains 1 or 2 heteroatoms independently selectedfrom N, O or S; wherein each said C₁₋₆ aliphatic, each said C₃₋₈cycloaliphatic ring and each said 4 to 8-membered heterocyclic ring, isoptionally and independently substituted with up to 3 instances of R⁷;or alternatively, two J^(C) groups attached to two vicinal ring C atoms,taken together with said two vicinal ring C atoms, form a 5 to7-membered heterocycle resulting in a fused ring C; wherein said 5 to7-membered heterocycle contains from 1 to 2 heteroatoms independentlyselected from N, O or S;

each R^(H) is independently selected from hydrogen, a C₁₋₆ aliphatic, aC₃₋₈ cycloaliphatic ring or a 4 to 8-membered heterocyclic ring; whereineach said 4 to 8-membered heterocylic ring contains between 1 and 3heteroatoms independently selected from O, N or S; and wherein each saidC₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring, each said 4 to8-membered heterocyclic ring, is optionally and independentlysubstituted with up to 3 instances of R⁷;

alternatively, two instances of R^(H) linked to the same nitrogen atomof J^(C), together with said nitrogen atom of J^(C), form a 4 to8-membered heterocyclic ring or a 5-membered heteroaryl ring; whereineach said 4 to 8-membered heterocyclic ring and each said 5-memberedheteroaryl ring optionally contains up to 2 additional heteroatomsindependently selected from N, O or S, and wherein each said 4 to8-membered heterocyclic ring and each said 5-membered heteroaryl ring isoptionally and independently substituted by up to 3 instances of R⁷; or

each R⁷ is independently selected from halogen, —CN, —NO₂, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —N(R⁸)₂, or an oxo group;wherein each said cycloalkyl group is optionally and independentlysubstituted with up to 3 instances of halogen;

each R⁸ is independently selected from hydrogen, a C₁₋₄ alkyl, C₁₋₄haloalkyl or a C₃₋₈ cycloalkyl ring; wherein each said cycloalkyl groupis optionally and independently substituted with up to 3 instances ofhalogen;

alternatively, two instances of R⁸ linked to the same nitrogen atom ofR⁷, together with said nitrogen atom of R⁷, form a 5 to 8-memberedheterocyclic ring or a 5-membered heteroaryl ring; wherein each said 5to 8-membered heterocyclic ring and each said 5-membered heteroaryl ringoptionally contains up to 2 additional heteroatoms independentlyselected from N, O or S; and

-   -   R^(A) is selected from hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄        haloalkyl; provided that the compound is not one of the        compounds represented below:

In some of the embodiments of the compound of Formula IA or IB, or apharmaceutically acceptable salt thereof, ring B is phenyl.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, n is an integer selected from 1 to 3, whereineach J^(B) is independently selected from halogen, a C₁₋₆ aliphatic or—OR^(B). In further embodiments, each J^(B) is independently selectedfrom halogen atoms. In still further embodiments, each J^(B) isindependently selected from fluoro or chloro. In yet furtherembodiments, each J^(B) is fluoro.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, n is an integer selected from 1 to 3, and eachJ^(B) is a C₁₋₆ aliphatic. In further embodiments, each J^(B) is methylor ethyl.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, n is 1. In further embodiments, J^(B) isselected from halogen atoms. In still further embodiments, J^(B) isfluoro or chloro. In yet further embodiments, J^(B) is fluoro.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, n is an integer selected from 1 to 3, and eachJ^(B) is independently selected from halogen, a C₁₋₆ aliphatic or—OR^(B). In further embodiments, at least one J^(B) is ortho to theattachment of the methylene linker between ring B and the triazolylring. In still further embodiments, each J^(B) is independently selectedfrom halogen atoms. In yet further embodiments, each J^(B) isindependently selected from fluoro or chloro. In yet still furtherembodiments, each J^(B) is fluoro.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, n is 1, and each J^(B) is independentlyselected from halogen, a C₁₋₆ aliphatic or —OR^(B), wherein at least oneof the J^(B) groups is ortho to the attachment of the methylene linkerbetween ring B and the triazolyl ring is fluoro.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, ring B is a 6-membered heteroaryl ring.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, ring B is a pyridyl or pyrimidinyl ring.

In some of the embodiments of Formula IA, or a pharmaceuticallyacceptable salt thereof, X in ring D of Formula AI is a ring carbon atomand it is optionally substituted. In further embodiments, ring B is aphenyl ring or 6-membered heteroaryl ring. In still further embodiments,ring B is phenyl. Alternatively, in some of the embodiments, ring B ispyridyl or pyrimidinyl ring.

In some of the embodiments of Formula IA, or a pharmaceuticallyacceptable salt thereof, X in ring D of Formula AI is a ring nitrogenatom.

In some of the embodiments of Formula IB, or a pharmaceuticallyacceptable salt thereof, one of the 4 instances of Y in ring D isselected from N, O or S and the other 3 instances of Y in ring D arecarbon atoms, wherein said carbon atoms are optionally substituted.

In some of the embodiments of the compounds of Formula IB, or apharmaceutically acceptable salt thereof, ring D is a thiazolyl oroxazolyl ring such as thiazol-2-yl, thiazol-4-yl, oxazol-2-yl oroxazol-4-yl ring. In further embodiments of the compounds of Formula IB,R^(C) is ring C, and ring C is a pyridyl, pyrimidinyl, oxazolyl orthiazol ring.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, m is 0.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, m is an integer selected from 1, 2 or 3 andeach J^(D) is independently selected from halogen, a C₁₋₆ aliphatic,—N(R^(D))₂, —N(Rd)C(O)R^(D), —N(Rd)C(O)OR^(D), —SO₂R^(D), —SO₂N(R^(D))₂,—N(R^(d))SO₂R^(D), —SRS, —OR^(D) or an optionally substituted C₃₋₈cycloaliphatic ring. In further embodiments, each J^(D) is independentlyselected from halogen atoms. In still further embodiments, each J^(D) isindependently selected from a chloro or fluoro.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, m is an integer selected from 1, 2 or 3 andeach J^(D) is independently selected from a C₁₋₆ aliphatic or a C₃₋₈cycloaliphatic ring. In further embodiments, each J^(D) is independentlymethyl, ethyl, propyl, cyclobutyl, cyclopropyl or isopropyl. In stillfurther embodiments, each J^(D) is independently methyl, ethyl orcyclopropyl.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, m is an integer selected from 1, 2 or 3 andeach J^(D) is independently selected from —N(RD)₂, —N(Rd)C(O)R^(D),—N(Rd)C(O)OR^(D), —SO₂R^(D), —SO₂N(RD)₂, —N(Rd)SO₂R^(D) or —OR^(D). Infurther embodiments, each R^(d) is independently selected from a C₁₋₄alkyl or hydrogen and each R^(D) is independently selected from hydrogenor C₁₋₄ alkyl. In still further embodiments, each R^(d) is independentlyselected from hydrogen or methyl, and each R^(D) is independentlyselected from hydrogen, methyl, ethyl, propyl or isopropyl. In yetfurther embodiments, each R^(d) and each R^(D) is independently selectedfrom hydrogen or methyl.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, m is an integer selected from 1, 2 or 3 andeach J^(D) is independently selected from methyl, fluoro, —N(R¹)₂,—N(R^(d))C(O)R^(D), —N(Rd)C(O)OR^(D), —SO₂R^(D), —SO₂N(R^(D))₂ or—N(R^(d))SO₂R^(D); wherein each R^(d) and each R^(D) is independentlyselected from hydrogen or methyl. In further embodiments, R^(C) is —CNor halo. Alternatively, R^(C) is a C₁₋₆ alkyl. In other alternativeembodiments, R^(C) is ring C. In some of the alternative embodiments,R^(C) is ring C, wherein ring C is a phenyl ring, a monocyclic 5 or6-membered heteroaryl ring, a monocyclic 3 to 10-membered cycloaliphaticring or a monocyclic 4 to 10-membered heterocycle; each of the phenylring, a monocyclic 5 or 6-membered heteroaryl ring, a monocyclic 3 to10-membered cycloaliphatic ring or a monocyclic 4 to 10-memberedheterocycle is optionally and independently substituted with up to 6instances of J^(C).

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is —CN or halo.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is a C₁₋₆ alkyl. In further embodiments,R^(C) is selected from methyl, ethyl, propyl, isopropyl or butyl.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is a ring C. In further embodiments, ringC is a phenyl ring, a monocyclic 5 or 6-membered heteroaryl ring, amonocyclic 3 to 10-membered cycloaliphatic ring or a monocyclic 4 to10-membered heterocycle; each of the phenyl ring, a monocyclic 5 or6-membered heteroaryl ring, a monocyclic 3 to 10-membered cycloaliphaticring or a monocyclic 4 to 10-membered heterocycle is optionally andindependently substituted with up to 6 instances of J^(C). In stillfurther embodiments, ring C is a phenyl, a monocyclic 5 or 6-memberedheteroaryl ring, a monocyclic 3 to 6-membered cycloaliphatic ring or amonocyclic 4 to 6-membered heterocycle; each of them optionally andindependently substituted with up to 3 instances of J^(C).

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is a ring C, wherein ring C is amonocyclic 3 to 6-membered cycloaliphatic ring, optionally substitutedwith up to 2 instances of J^(C). In further embodiments, ring C iscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is a ring C, wherein ring C is a4-membered cycloaliphatic ring substituted by 1 to 3 instances of J^(C),a 5-membered cycloaliphatic ring substituted by 1 to 4 instances ofJ^(C) or a 6-membered cycloaliphatic ring substituted by 1 to 5instances of J^(C), and wherein each J^(C) is independently selectedfrom halogen or C₁₋₆ aliphatic.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is a ring C, wherein ring C is phenyl,optionally and independently substituted by up to 5 instances of J^(C).In further embodiments, R^(C) is ring C and ring C is unsubstitutedphenyl.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is ring C and ring C is substitutedphenyl. In further embodiments, ring C is substituted by 1 to 3instances of J^(C) and wherein each J^(C) is independently selected fromhalogen, C₁₋₆ aliphatic, —NH₂, —CN or —O(C₁₋₆ aliphatic). In stillfurther embodiments, each J^(C) is independently selected from halogen,C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —CN or —NH₂. In yet further embodiments,ring C is phenyl substituted by 1 to 2 instances of J^(C). In yet stillfurther embodiments, each J^(C) is independently selected from fluoro,methyl, —CN or —OCH₃.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is ring C, wherein ring C is a 5 to6-membered heteroaryl ring, optionally substituted by up to 5 instancesof J^(C).

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is ring C, wherein ring C is anunsubstituted 5 to 6-membered heteroaryl ring. In further embodiments,the 5 to 6-membered heteroaryl ring as ring C is selected from thienyl,thiazolyl, oxadiazolyl, oxazolyl, isooxazolyl, tetrazolyl, pyrrolyl,triazolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl. Instill further embodiments, the 5 to 6-membered heteroaryl ring as ring Cis selected from furanyl, thienyl, thiazolyl, oxazolyl,1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl or pyrazin-3-yl. In yetfurther embodiments, the 5 to 6-membered heteroaryl ring as ring C isselected from thienyl, thiazolyl, oxazoly, 1,3,4-oxadiazolyl orpyridinyl. In yet still further embodiments, the 5 to 6-memberedheteroaryl ring as ring C is selected from furan-2-yl, furan-3-yl,thien-3-yl, thien-2-yl, thiazol-2-yl, thiazol-4-yl, oxazol-2-yl,oxazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl orpyrimidin-4-yl.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is ring C, wherein ring C is a 5 to6-membered heteroaryl ring substituted by up to 5 instances of J^(C). Infurther embodiments, the 5 to 6-membered heteroaryl ring as ring C isselected from thienyl, thiazolyl, oxadiazolyl, oxazolyl, isooxazolyl,tetrazolyl, pyrrolyl, triazolyl, furanyl, pyridinyl, pyrimidinyl,pyrazinyl or pyridazinyl. In still further embodiments, the 5 to6-membered heteroaryl ring as ring C is selected from furanyl, thienyl,thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl orpyrazin-3-yl. In yet further embodiments, the 5 to 6-membered heteroarylring as ring C is selected from thienyl, thiazolyl, oxazolyl,1,3,4-oxadiazolyl or pyridinyl. In yet still further embodiments, the 5to 6-membered heteroaryl ring as ring C is selected from furan-2-yl,furan-3-yl, thien-3-yl, thien-2-yl, thiazol-2-yl, thiazol-4-yl,oxazol-2-yl, oxazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,pyrimidin-2-yl or pyrimidin-4-yl; and is independently substituted withup to 2 instances of r. In some of the embodiments, each J^(C) isindependently selected from halogen, C₁₋₆ aliphatic, —CN, —NH₂ or—O(C₁₋₆ aliphatic).

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, R^(C) is ring C, wherein ring C is thienyl orpyridinyl substituted by 1 to 3 instances of J^(C) and each J^(C) isindependently selected from a halogen, C₁₋₆ aliphatic, —NH₂ or —O(C₁₋₆aliphatic). In further embodiments, each J^(C) is independently selectedfrom C₁₋₆ aliphatic. In still further embodiments, each J^(C) isindependently selected from methyl, ethyl, propyl or isopropyl. In yetfurther embodiments, each J^(C) is independently selected from a halogenatom, methyl, —NH₂ or —OCH₃.

In some of the embodiments of Formula IA or IB, or a pharmaceuticallyacceptable salt thereof, RC is ring C, wherein ring C is a bicyclic 7 to10-membered heteroaryl ring. In further embodiments, ring C isbenzofuran-2-yl, furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl,benzothienyl or indolyl. In still further embodiments, ring C isbenzofuran-2-yl, furo[3,2-b]pyridinyl or benzothienyl.

In some of the embodiments, the invention is directed to the compoundhaving Formula IA, or a pharmaceutically acceptable salt thereof

In some of the embodiments of the compound of Formula IA, or apharmaceutically acceptable salt thereof, the compound has Formula IIA,

In some of the embodiments of the compound of Formula IA, or apharmaceutically acceptable salt thereof, the compound has Formula IIIor Formula IV:

In further embodiments, the compound has one of Formulae VA, VC, VD andVF:

In some of the embodiments, the invention is directed to the compound ofFormula IB, or a pharmaceutically acceptable salt thereof. In furtherembodiments, the compound has Formula IIB:

In some of the embodiments of the compound of Formula IIB, R^(C) ishalo, —CN or —C₁₋₆ alkyl.

In some of the embodiments of the compound of Formula IIB, R^(C) is —CNand the compound is represented by Formula VI:

In some of the embodiments of the compound of Formula IIB, R^(C) is ringC and the compound is represented by Formula VII:

wherein the symbol of the encircled letter C represents ring C. Infurther embodiments, ring C is selected from a phenyl ring, a monocyclic5 or 6-membered heteroaryl ring, a monocyclic 3 to 10-memberedcycloaliphatic ring, or a monocyclic 4, 5 or 6-membered heterocycle;wherein each of said phenyl ring, monocyclic 5 or 6-membered heteroarylring, monocyclic 3 to 8-membered cycloaliphatic ring, or monocyclic 4, 5or 6-membered heterocycle is optionally and independently substitutedwith up to 3 instances of J^(C). In still further embodiments, ring C isselected from a phenyl ring, cyclopropyl ring, cyclobutyl ring,azetidinyl ring, thiazolyl ring or oxazolyl ring. In yet furtherembodiments, ring C is a thiazolyl ring or oxazolyl ring, e.g.,thiazol-2-yl ring, thiazol-4-yl ring, oxazol-2-yl ring and oxazol-4-ylring. In yet still further embodiments, ring C is a thiazol-2-yl ring orthiazol-4-yl ring.

In some embodiments, compounds of Formula IA and Formula IB are selectedfrom those listed in Tables 1a and 1b herein.

TABLE 1b

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

TABLE 1b

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67A

I-67B

I-68

Methods of Preparing the Compounds

The compounds of Formula IA or Formula IB may be prepared according tothe schemes and examples depicted and described below. Unless otherwisespecified, the starting materials and various intermediates may beobtained from commercial sources, prepared from commercially availablecompounds or prepared using well-known synthetic methods. Another aspectof the present invention is a process for preparing the compounds ofFormula IA or Formula IB as disclosed herein.

General synthetic procedures for the compounds of this invention aredescribed below. The synthetic schemes are presented as examples and donot limit the scope of the invention in any way.

General Procedure A

Step 1: Triazole Formation:

A mixture of hydrazide A (1.0 eq) and amidine B (1.0 eq) in EtOH (0.05to 0.3 M depending on solubility) in a sealed vial is heated, e.g., toabout 100-110° C. (bath temperature) and monitored by LC/MS analysis.Once complete (reaction time typically 24 h), the reaction mixture isconcentrated, azeotroped with toluene and dried in vacuo to affordtriazole C as the hydrochloride salt. It is carried on to alkylationstep without any further purification.

Step 2: Alkylation:

Triazole C is dissolved in DMF and treated with sodium hydride (e.g.,about 60% w/w in mineral oil, about 2.0 eq) and the appropriate benzylbromide (e.g., about 1.5 eq). The reaction is stirred at roomtemperature and monitored by LC/MS analysis. Once complete (reactiontime typically 30 min), the reaction solution is diluted with ethylacetate and washed with water (e.g., 4 times) and brine. The organiclayer is dried, e.g., over MgSO₄ or Na₂SO4, filtered and concentrated.The crude material is purified using SiO2 chromatography and anappropriate solvent gradient (ethyl acetate/hexanes or DCM/methanol) toafford products D and E. In all cases, the two regioisomers are readilyseparable. Structural assignments are based on 1H NMR analysis andconfirmed by observed activities in biological assays.

General Procedure B

Amidine Formation:

Nitrile F is treated with sodium methoxide (e.g., about 0.5 M inmethanol, about 0.5 eq) at room temperature and monitored by LC/MSanalysis. Once the starting nitrile is consumed (reaction time wastypically 2-7 h), ammonium chloride (e.g., about 1.1 eq) is added andthe reaction mixture is stirred for about 16-24 h. The reaction mixtureis concentrated and dried in vacuo. In some case, the crude amidine iscollected by filtration.

The crude amidine is then used as one of the starting compounds inGeneral Procedure A described above without any further purification toyield Compounds D and E.

General Procedure C

A solution of2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16), inDMA is treated with a large excess of azetidine (e.g., ˜30 eq). Theresultant solution is warmed to about 100° C. and stirred at thattemperature for about 18 h. The reaction solution is cooled to roomtemperature, poured into 1N NaOH solution and then extracted with EtOAc.The organic phases are dried, e.g., over MgSO4 or Na2SO4, filtered andconcentrated. The crude product is purified using SiO2 chromatographyand an appropriate gradient (MeOH—CH3CN (1:7)/CH2Cl2) to yield2-(5-(azetidin-1-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine(1-23) as a solid.

General Procedure D

A solution of pyrazole (1.1 eq) in DMF is treated with sodium hydride(e.g., about 60% w/w in mineral oil, about 1.2 eq) and stirred for about10 min at room temperature.2-(5-Bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16,e.g., 1.0 eq) is then added. The resultant mixture is warmed to about50° C. and stirred at that temperature for about 1 h. The reactionsolution is cooled to room temperature, poured into water, and filteredto yield2-(1-(2-fluorobenzyl)-5-(1H-pyrazol-1-yl)-1H-1,2,4-triazol-3-yl)pyridine(I-10) as a solid.

General Procedure E

To a solution of2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (1-16,e.g., about 0.95 g, 2.9 mmol) in N,N-dimethylformamide (e.g., 9.5 mL) isadded potassium cyanide (e.g., about 0.928 g, 14.3 mmol). After heatingthe solution at about 100° C. for about 22 h, the solution is dilutedwith ethyl acetate (e.g., about 125 mL) and water (e.g., about 100 mL).The layers are separated, and the aqueous layer is extracted with ethylacetate (e.g., about 2×50 mL). The organics are combined, washed withwater (e.g., about 50 mL) and brine (e.g., about 50 mL), dried, e.g.,over sodium sulfate or magnesium sulfate, filtered, and the solvent isremoved in vacuo to give the crude product, I-33. Purification by silicagel chromatography (0-15% ethyl acetate in dichloromethane) yields1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrileI-33 (1-33) as a solid.

To a solution of1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile(I-33, e.g., about 100 mg, 0.358 mmol) and potassium carbonate (e.g.,about 198 mg, 1.43 mmol) in methanol (e.g., about 3.6 mL) is addedhydroxylamine hydrochloride (e.g., about 75 mg, 1.1 mmol). The solutionis heated to about 70° C. for about 1.25 h, at which point the solutionis diluted with ethyl acetate (e.g., about 20 mL) and the solids arefiltered off through a cotton plug. The solvent is removed in vacuo andthe crude residue is diluted with water (e.g., about 50 mL) and amixture of dichloromethane and 2-propanol, e.g., a 5:1 mixture ofdichloromethane and 2-propanol (e.g., about 50 mL). The layers areseparated and the organic layer is washed with water (e.g., about 50mL), dried, e.g., over sodium sulfate or magnesium sulfate, and thesolvent is removed in vacuo. To the resulting crude1-(2-fluorobenzyl)-N′-hydroxy-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboximidamideis added trimethyl orthorfomate (e.g., about 4.5 mL, 41 mmol) and acatalytic amount of p-toluensulfonic acid monohydrate (e.g., about 3.4mg, 0.018 mmol). The solution is heated to about 100° C. for about 1.5h, and the excess orthoformate is removed in vacuo to give the crudeproduct, I-34. Purification by silica gel chromatography (e.g., 20-80%ethyl acetate in hexanes) yields3-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,2,4-oxadiazole,I-34, as a solid.

General Procedure F

In the compounds of Formula IA or IB, any bromo substituent on ring D,i.e., when J^(D) is Br, can be converted into an amino substituent withthe procedure as shown below to obtain the corresponding compound having—NH₂ as J^(D). Similarly, any bromo substituent on ring C, i.e., whenJ^(C) is Br, in a compound of Formula IA or IB can be converted into anamino substituent with the procedure as shown below to obtain thecorresponding compound having —NH₂ as J^(C). In the reaction schemedescribed below, compound I-19 is used as an example to demonstrate theconversion of a bromo ring substituent, e.g., Br as J^(D), to an aminoring substituent, e.g., —NH₂ as J^(D), in a compound of Formula IA orIB.

To a suspension of2-(3-(6-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole(I-19) and copper(I) oxide (e.g., about 0.2 eq) in ethyleneglycol-dioxane (e.g., about 4:1) in a sealed tube is added ammoniumhydroxide solution (e.g., —29% in water, —30 eq). The resultant mixtureis warmed to about 100° C. and stirred at that temperature for about 24h. The reaction solution is cooled to room temperature, poured into 1NNaOH solution and then extracted with EtOAc. The organic phases aredried, e.g., over Na₂SO₄ or MgSO₄, filtered and concentrated. The crudeproduct is purified using SiO2 chromatography and an appropriategradient (EtOAc/hexanes) to give6-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-2-amine(I-14) as a solid.

Pharmaceutically Acceptable Salts

The phrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofFormula IA or Formula IB. For use in medicine, the salts of thecompounds of Formula IA or Formula IB will be pharmaceuticallyacceptable salts. Other salts may, however, be useful in the preparationof the compounds of Formula IA or Formula IB or of theirpharmaceutically acceptable salts. A pharmaceutically acceptable saltmay involve the inclusion of another molecule such as an acetate ion, asuccinate ion or other counter ion. The counter ion may be any organicor inorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. Instances where multiple charged atomsare part of the pharmaceutically acceptable salt can have multiplecounter ions. Hence, a pharmaceutically acceptable salt can have one ormore charged atoms and/or one or more counter ion.

Pharmaceutically acceptable salts of the compounds described hereininclude those derived from suitable inorganic and organic acids andbases. In some embodiments, the salts can be prepared in situ during thefinal isolation and purification of the compounds. In other embodimentsthe salts can be prepared from the free form of the compound in aseparate synthetic step.

When the compound of Formula IA or Formula IB is acidic or contains asufficiently acidic bioisostere, suitable “pharmaceutically acceptablesalts” refers to salts prepared form pharmaceutically acceptablenon-toxic bases including inorganic bases and organic bases. Saltsderived from inorganic bases include aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc and the like. Particular embodiments includeammonium, calcium, magnesium, potassium and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as arginine, betaine, caffeine, choline, N,N.sup.1-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine tripropylamine, tromethamineand the like.

When the compound of Formula IA or Formula IB is basic or contains asufficiently basic bioisostere, salts may be prepared frompharmaceutically acceptable non-toxic acids, including inorganic andorganic acids. Such acids include acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particular embodiments include citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric and tartaric acids. Other exemplary saltsinclude, but are not limited, to sulfate, citrate, acetate, oxalate,chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidphosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate,oleate, tannate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, and palmoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19, incorporated here by reference in its entirety.

Pharmaceutical Compositions and Methods of Administration

The compounds herein disclosed, and their pharmaceutically acceptablesalts, may be formulated as pharmaceutical compositions or“formulations”.

A typical formulation is prepared by mixing a compound of Formula IA orFormula IB, or a pharmaceutically acceptable salt thereof, and acarrier, diluent or excipient. Suitable carriers, diluents andexcipients are well known to those skilled in the art and includematerials such as carbohydrates, waxes, water soluble and/or swellablepolymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents,water, and the like. The particular carrier, diluent or excipient usedwill depend upon the means and purpose for which the compound of FormulaIA or Formula IB is being formulated. Solvents are generally selectedbased on solvents recognized by persons skilled in the art as safe(GRAS-Generally Regarded as Safe) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include other types of excipients such as one ormore buffers, stabilizing agents, antiadherents, surfactants, wettingagents, lubricating agents, emulsifiers, binders, suspending agents,disintegrants, fillers, sorbents, coatings (e.g. enteric or slowrelease) preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of Formula IA or Formula IB or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof Formula IA or Formula IB, a pharmaceutically acceptable salt thereof,wherein the compound of Formula IA or IB, or its pharmaceuticallyacceptable salt, can be in a stabilized form, such as a complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more of the excipientsdescribed above. A compound having the desired degree of purity isoptionally mixed with pharmaceutically acceptable diluents, carriers,excipients or stabilizers, in the form of a lyophilized formulation,milled powder, or an aqueous solution. Formulation may be conducted bymixing at ambient temperature at the appropriate pH, and at the desireddegree of purity, with physiologically acceptable carriers. The pH ofthe formulation depends mainly on the particular use and theconcentration of compound, but may range from about 3 to about 8. Whenthe agent described herein is a solid amorphous dispersion formed by asolvent process, additives may be added directly to the spray-dryingsolution when forming the mixture such as the additive is dissolved orsuspended in the solution as a slurry which can then be spray dried.Alternatively, the additives may be added following spray-drying processto aid in the forming of the final formulated product.

The compound of Formula IA or Formula IB or a pharmaceuticallyacceptable salt thereof, is typically formulated into pharmaceuticaldosage forms to provide an easily controllable dosage of the drug and toenable patient compliance with the prescribed regimen. Pharmaceuticalformulations of compounds of Formula IA or Formula IB, or apharmaceutically acceptable salt thereof, may be prepared for variousroutes and types of administration. Various dosage forms may exist forthe same compound, since different medical conditions may warrantdifferent routes of administration.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thesubject treated and the particular mode of administration. For example,a time-release formulation intended for oral administration to humansmay contain approximately 1 to 1000 mg of active material compoundedwith an appropriate and convenient amount of carrier material which mayvary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provideeasily measurable amounts for administration. For example, an aqueoussolution intended for intravenous infusion may contain from about 3 to500 μg of the active ingredient per milliliter of solution in order thatinfusion of a suitable volume at a rate of about 30 mL/hr can occur. Asa general proposition, the initial pharmaceutically effective amount ofthe inhibitor administered will be in the range of about 0.01-100 mg/kgper dose, namely about 0.1 to 20 mg/kg of patient body weight per day,with the typical initial range of compound used being 0.3 to 15mg/kg/day.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician. The therapeutically or pharmaceutically effectiveamount of the compound to be administered will be governed by suchconsiderations, and is the minimum amount necessary to ameliorate, cureor treat the disease or disorder or one or more of its symptoms.

The pharmaceutical compositions of Formula IA or Formula IB will beformulated, dosed, and administered in a fashion, i.e., amounts,concentrations, schedules, course, vehicles, and route ofadministration, consistent with good medical practice. Factors forconsideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners, suchas the age, weight, and response of the individual patient.

The term “prophylactically effective amount” refers to an amounteffective in preventing or substantially lessening the chances ofacquiring a disease or disorder or in reducing the severity of thedisease or disorder before it is acquired or reducing the severity ofone or more of its symptoms before the symptoms develop. Roughly,prophylactic measures are divided between primary prophylaxis (toprevent the development of a disease) and secondary prophylaxis (wherebythe disease has already developed and the patient is protected againstworsening of this process).

Acceptable diluents, carriers, excipients, and stabilizers are thosethat are nontoxic to recipients at the dosages and concentrationsemployed, and include buffers such as phosphate, citrate, and otherorganic acids; antioxidants including ascorbic acid and methionine;preservatives (such as octadecyldimethylbenzyl ammonium chloride;hexamethonium chloride; benzalkonium chloride, benzethonium chloride;phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol);proteins, such as serum albumin, gelatin, or immunoglobulins;hydrophilic polymers such as polyvinylpyrrolidone; amino acids such asglycine, glutamine, asparagine, histidine, arginine, or lysine;monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, or dextrins; chelating agents such as EDTA; sugarssuch as sucrose, mannitol, tretralose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g. Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ orpolyethylene glycol (PEG). The active pharmaceutical ingredients mayalso be entrapped in microcapsules prepared, for example, bycoacervation techniques or by interfacial polymerization, e.g.,hydroxymethylcellulose or gelatin-microcapsules andpoly-(methylmethacrylate) microcapsules, respectively; in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington's: The Science and Practiceof Pharmacy, 21^(st) Edition, University of the Sciences inPhiladelphia, Eds., 2005 (hereafter “Remington's”).

“Controlled drug delivery systems” supply the drug to the body in amanner precisely controlled to suit the drug and the conditions beingtreated. The primary aim is to achieve a therapeutic drug concentrationat the site of action for the desired duration of time. The term“controlled release” is often used to refer to a variety of methods thatmodify release of drug from a dosage form. This term includespreparations labeled as “extended release”, “delayed release”, “modifiedrelease” or “sustained release”. In general, one can provide forcontrolled release of the agents described herein through the use of awide variety of polymeric carriers and controlled release systemsincluding erodible and non-erodible matrices, osmotic control devices,various reservoir devices, enteric coatings and multiparticulate controldevices.

“Sustained-release preparations” are the most common applications ofcontrolled release. Suitable examples of sustained-release preparationsinclude semipermeable matrices of solid hydrophobic polymers containingthe compound, which matrices are in the form of shaped articles, e.g.films, or microcapsules. Examples of sustained-release matrices includepolyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate),or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919),copolymers of L-glutamic acid and gamma-ethyl-L-glutamate,non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolicacid copolymers, and poly-D-(−)-3-hydroxybutyric acid.

“Immediate-release preparations” may also be prepared. The objective ofthese formulations is to get the drug into the bloodstream and to thesite of action as rapidly as possible. For instance, for rapiddissolution, most tablets are designed to undergo rapid disintegrationto granules and subsequent deaggregation to fine particles. Thisprovides a larger surface area exposed to the dissolution medium,resulting in a faster dissolution rate.

Agents described herein can be incorporated into an erodible ornon-erodible polymeric matrix controlled release device. By an erodiblematrix is meant aqueous-erodible or water-swellable or aqueous-solublein the sense of being either erodible or swellable or dissolvable inpure water or requiring the presence of an acid or base to ionize thepolymeric matrix sufficiently to cause erosion or dissolution. Whencontacted with the aqueous environment of use, the erodible polymericmatrix imbibes water and forms an aqueous-swollen gel or matrix thatentraps the agent described herein. The aqueous-swollen matrix graduallyerodes, swells, disintegrates or dissolves in the environment of use,thereby controlling the release of a compound described herein to theenvironment of use. One ingredient of this water-swollen matrix is thewater-swellable, erodible, or soluble polymer, which may generally bedescribed as an osmopolymer, hydrogel or water-swellable polymer. Suchpolymers may be linear, branched, or cross linked. The polymers may behomopolymers or copolymers. In certain embodiments, they may besynthetic polymers derived from vinyl, acrylate, methacrylate, urethane,ester and oxide monomers. In other embodiments, they can be derivativesof naturally occurring polymers such as polysaccharides (e.g. chitin,chitosan, dextran and pullulan; gum agar, gum arabic, gum karaya, locustbean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthangum and scleroglucan), starches (e.g. dextrin and maltodextrin),hydrophilic colloids (e.g. pectin), phosphatides (e.g. lecithin),alginates (e g ammonium alginate, sodium, potassium or calcium alginate,propylene glycol alginate), gelatin, collagen, and cellulosics.Cellulosics are cellulose polymer that has been modified by reaction ofat least a portion of the hydroxyl groups on the saccharide repeat unitswith a compound to form an ester-linked or an ether-linked substituent.For example, the cellulosic ethyl cellulose has an ether linked ethylsubstituent attached to the saccharide repeat unit, while the cellulosiccellulose acetate has an ester linked acetate substituent. In certainembodiments, the cellulosics for the erodible matrix comprisesaqueous-soluble and aqueous-erodible cellulosics can include, forexample, ethyl cellulose (EC), methylethyl cellulose (MEC),carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulosepropionate (CP), cellulose butyrate (CB), cellulose acetate butyrate(CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS,hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), andethylhydroxy ethylcellulose (EHEC). In certain embodiments, thecellulosics comprises various grades of low viscosity (MW less than orequal to 50,000 daltons, for example, the Dow Methocel™ series E5,E15LV, E50LV and K100LY) and high viscosity (MW greater than 50,000daltons, for example, E4MCR, E10MCR, K4M, K15M and K100M and theMethocel™ K series) HPMC. Other commercially available types of HPMCinclude the Shin Etsu Metolose 90SH series.

Other materials useful as the erodible matrix material include, but arenot limited to, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol,polyvinyl acetate, glycerol fatty acid esters, polyacrylamide,polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid(EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.) and other acrylic acidderivatives such as homopolymers and copolymers of butylmethacrylate,methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl)methacrylate chloride.

Alternatively, the agents of the present invention may be administeredby or incorporated into a non-erodible matrix device. In such devices,an agent described herein is distributed in an inert matrix. The agentis released by diffusion through the inert matrix. Examples of materialssuitable for the inert matrix include insoluble plastics (e.g methylacrylate-methyl methacrylate copolymers, polyvinyl chloride,polyethylene), hydrophilic polymers (e.g. ethyl cellulose, celluloseacetate, cross linked polyvinylpyrrolidone (also known ascrospovidone)), and fatty compounds (e.g. carnauba wax, microcrystallinewax, and triglycerides). Such devices are described further inRemington: The Science and Practice of Pharmacy, 20th edition (2000).

As noted above, the agents described herein may also be incorporatedinto an osmotic control device. Such devices generally include a corecontaining one or more agents as described herein and a water permeable,non-dissolving and non-eroding coating surrounding the core whichcontrols the influx of water into the core from an aqueous environmentof use so as to cause drug release by extrusion of some or all of thecore to the environment of use. In certain embodiments, the coating ispolymeric, aqueous-permeable, and has at least one delivery port. Thecore of the osmotic device optionally includes an osmotic agent whichacts to imbibe water from the surrounding environment via such asemi-permeable membrane. The osmotic agent contained in the core of thisdevice may be an aqueous-swellable hydrophilic polymer or it may be anosmogen, also known as an osmagent. Pressure is generated within thedevice which forces the agent(s) out of the device via an orifice (of asize designed to minimize solute diffusion while preventing the build-upof a hydrostatic pressure head). Non limiting examples of osmoticcontrol devices are disclosed in U.S. patent application Ser. No.09/495,061.

The amount of water-swellable hydrophilic polymers present in the coremay range from about 5 to about 80 wt % (including for example, 10 to 50wt %). Non limiting examples of core materials include hydrophilic vinyland acrylic polymers, polysaccharides such as calcium alginate,polyethylene oxide (PEO), polyethylene glycol (PEG), polypropyleneglycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic) acid,poly (methacrylic) acid, polyvinylpyrrolidone (PVP) and cross linkedPVP, polyvinyl alcohol (PVA), PVA/PVP copolymers and PVA/PVP copolymerswith hydrophobic monomers such as methyl methacrylate, vinyl acetate,and the like, hydrophilic polyurethanes containing large PEO blocks,sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC),carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodiumalginate, polycarbophil, gelatin, xanthan gum, and sodium starchglycolat. Other materials include hydrogels comprising interpenetratingnetworks of polymers that may be formed by addition or by condensationpolymerization, the components of which may comprise hydrophilic andhydrophobic monomers such as those just mentioned. Water-swellablehydrophilic polymers include but are not limited to PEO, PEG, PVP,sodium croscarmellose, HPMC, sodium starch glycolate, polyacrylic acidand cross linked versions or mixtures thereof

The core may also include an osmogen (or osmagent). The amount ofosmogen present in the core may range from about 2 to about 70 wt %(including, for example, from 10 to 50 wt %). Typical classes ofsuitable osmogens are water-soluble organic acids, salts and sugars thatare capable of imbibing water to thereby effect an osmotic pressuregradient across the barrier of the surrounding coating. Typical usefulosmogens include but are not limited to magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassiumchloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, inositol,raffinose, sucrose, glucose, fructose, lactose, citric acid, succinicacid, tartaric acid, and mixtures thereof. In certain embodiments, theosmogen is glucose, lactose, sucrose, mannitol, xylitol, sodiumchloride, including combinations thereof

The rate of drug delivery is controlled by such factors as thepermeability and thickness of the coating, the osmotic pressure of thedrug-containing layer, the degree of hydrophilicity of the hydrogellayer, and the surface area of the device. Those skilled in the art willappreciate that increasing the thickness of the coating will reduce therelease rate, while any of the following will increase the release rate:increasing the permeability of the coating; increasing thehydrophilicity of the hydrogel layer; increasing the osmotic pressure ofthe drug-containing layer; or increasing the device's surface area.

In certain embodiments, entrainment of particles of agents describedherein in the extruding fluid during operation of such osmotic device isdesirable. For the particles to be well entrained, the agent drug formis dispersed in the fluid before the particles have an opportunity tosettle in the tablet core. One means of accomplishing this is by addinga disintegrant that serves to break up the compressed core into itsparticulate components. Non limiting examples of standard disintegrantsinclude materials such as sodium starch glycolate (e. g., Explotab™CLV), microcrystalline cellulose (e. g., Avicel™), microcrystallinesilicified cellulose (e. g., ProSoIv™) and croscarmellose sodium (e. g.,Ac-Di-Sol™), and other disintegrants known to those skilled in the art.Depending upon the particular formulation, some disintegrants workbetter than others. Several disintegrants tend to form gels as theyswell with water, thus hindering drug delivery from the device.Non-gelling, non-swelling disintegrants provide a more rapid dispersionof the drug particles within the core as water enters the core. Incertain embodiments, non-gelling, non-swelling disintegrants are resins,for example, ion-exchange resins. In one embodiment, the resin isAmberlite™ IRP 88 (available from Rohm and Haas, Philadelphia, Pa.).When used, the disintegrant is present in amounts ranging from about1-25% of the core agent.

Another example of an osmotic device is an osmotic capsule. The capsuleshell or portion of the capsule shell can be semipermeable. The capsulecan be filled either by a powder or liquid consisting of an agentdescribed herein, excipients that imbibe water to provide osmoticpotential, and/or a water-swellable polymer, or optionally solubilizingexcipients. The capsule core can also be made such that it has a bilayeror multilayer agent analogous to the bilayer, trilayer or concentricgeometries described above.

Another class of osmotic device useful in this invention comprisescoated swellable tablets, for example, as described in EP378404. Coatedswellable tablets comprise a tablet core comprising an agent describedherein and a swelling material, preferably a hydrophilic polymer, coatedwith a membrane, which contains holes, or pores through which, in theaqueous use environment, the hydrophilic polymer can extrude and carryout the agent. Alternatively, the membrane may contain polymeric or lowmolecular weight water-soluble porosigens. Porosigens dissolve in theaqueous use environment, providing pores through which the hydrophilicpolymer and agent may extrude. Examples of porosigens are water-solublepolymers such as HPMC, PEG, and low molecular weight compounds such asglycerol, sucrose, glucose, and sodium chloride. In addition, pores maybe formed in the coating by drilling holes in the coating using a laseror other mechanical means. In this class of osmotic devices, themembrane material may comprise any film-forming polymer, includingpolymers which are water permeable or impermeable, providing that themembrane deposited on the tablet core is porous or containswater-soluble porosigens or possesses a macroscopic hole for wateringress and drug release. Embodiments of this class of sustained releasedevices may also be multilayered, as described, for example, inEP378404.

When an agent described herein is a liquid or oil, such as a lipidvehicle formulation, for example as described in WO05/011634, theosmotic controlled-release device may comprise a soft-gel or gelatincapsule formed with a composite wall and comprising the liquidformulation where the wall comprises a barrier layer formed over theexternal surface of the capsule, an expandable layer formed over thebarrier layer, and a semipermeable layer formed over the expandablelayer. A delivery port connects the liquid formulation with the aqueoususe environment. Such devices are described, for example, in U.S. Pat.No. 6,419,952, U.S. Pat. No. 6,342,249, U.S. Pat. No. 5,324,280, U.S.Pat. No. 4,672,850, U.S. Pat. No. 4,627,850, U.S. Pat. No. 4,203,440,and U.S. Pat. No. 3,995,631.

As further noted above, the agents described herein may be provided inthe form of microparticulates, generally ranging in size from about 10μm to about 2 mm (including, for example, from about 100 μm to 1 mm indiameter). Such multiparticulates may be packaged, for example, in acapsule such as a gelatin capsule or a capsule formed from anaqueous-soluble polymer such as HPMCAS, HPMC or starch; dosed as asuspension or slurry in a liquid; or they may be formed into a tablet,caplet, or pill by compression or other processes known in the art. Suchmultiparticulates may be made by any known process, such as wet- anddry-granulation processes, extrusion/spheronization, roller-compaction,melt-congealing, or by spray-coating seed cores. For example, in wet-and dry-granulation processes, the agent described herein and optionalexcipients may be granulated to form multiparticulates of the desiredsize.

The agents can be incorporated into microemulsions, which generally arethermodynamically stable, isotropically clear dispersions of twoimmiscible liquids, such as oil and water, stabilized by an interfacialfilm of surfactant molecules (Encyclopedia of Pharmaceutical Technology,New York: Marcel Dekker, 1992, volume 9). For the preparation ofmicroemulsions, surfactant (emulsifier), co-surfactant (co-emulsifier),an oil phase and a water phase are necessary. Suitable surfactantsinclude any surfactants that are useful in the preparation of emulsions,e.g., emulsifiers that are typically used in the preparation of creams.The co-surfactant (or “co-emulsifier”) is generally selected from thegroup of polyglycerol derivatives, glycerol derivatives and fattyalcohols. Preferred emulsifier/co-emulsifier combinations are generallyalthough not necessarily selected from the group consisting of: glycerylmonostearate and polyoxyethylene stearate; polyethylene glycol andethylene glycol palmitostearate; and caprilic and capric triglyceridesand oleoyl macrogolglycerides. The water phase includes not only waterbut also, typically, buffers, glucose, propylene glycol, polyethyleneglycols, preferably lower molecular weight polyethylene glycols (e.g.,PEG 300 and PEG 400), and/or glycerol, and the like, while the oil phasewill generally comprise, for example, fatty acid esters, modifiedvegetable oils, silicone oils, mixtures of mono-di- and triglycerides,mono- and di-esters of PEG (e.g., oleoyl macrogol glycerides), etc.

The compounds described herein can be incorporated intopharmaceutically-acceptable nanoparticle, nanosphere, and nanocapsuleformulations (Delie and Blanco-Prieto, 2005, Molecule 10:65-80).Nanocapsules can generally entrap compounds in a stable and reproducibleway. To avoid side effects due to intracellular polymeric overloading,ultrafine particles (sized around 0.1 μm) can be designed using polymersable to be degraded in vivo (e.g. biodegradable polyalkyl-cyanoacrylatenanoparticles). Such particles are described in the prior art.

Implantable devices coated with a compound of this invention are anotherembodiment of the present invention. The compounds may also be coated onimplantable medical devices, such as beads, or co-formulated with apolymer or other molecule, to provide a “drug depot”, thus permittingthe drug to be released over a longer time period than administration ofan aqueous solution of the drug. Suitable coatings and the generalpreparation of coated implantable devices are described in U.S. Pat.Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typicallybiocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccharides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's. Such methods include the step of bringing into associationthe active ingredient with the carrier which constitutes one or moreaccessory ingredients. In general the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both, and then,if necessary, shaping the product.

The terms “administer”, “administering” or “administration” in referenceto a compound, composition or formulation of the invention meansintroducing the compound into the system of the animal in need oftreatment. When a compound of the invention is provided in combinationwith one or more other active agents, “administration” and its variantsare each understood to include concurrent and/or sequential introductionof the compound and the other active agents.

The compositions described herein may be administered systemically orlocally, e.g.: orally (e.g. using capsules, powders, solutions,suspensions, tablets, sublingual tablets and the like), by inhalation(e.g. with an aerosol, gas, inhaler, nebulizer or the like), to the ear(e.g. using ear drops), topically (e.g. using creams, gels, liniments,lotions, ointments, pastes, transdermal patches, etc), ophthalmically(e.g. with eye drops, ophthalmic gels, ophthalmic ointments), rectally(e.g. using enemas or suppositories), nasally, buccally, vaginally (e.g.using douches, intrauterine devices, vaginal suppositories, vaginalrings or tablets, etc), via an implanted reservoir or the like, orparenterally depending on the severity and type of the disease beingtreated. The term “parenteral” as used herein includes, but is notlimited to, subcutaneous, intravenous, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques. Preferably, thecompositions are administered orally, intraperitoneally orintravenously.

The pharmaceutical compositions described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. Liquiddosage forms for oral administration include, but are not limited to,pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. Tablets may be uncoated or may be coated by knowntechniques including microencapsulation to mask an unpleasant taste orto delay disintegration and adsorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed. A water soluble taste maskingmaterial such as hydroxypropyl-methylcellulose orhydroxypropyl-cellulose may be employed.

Formulations of a compound of Formula IA or Formula IB that are suitablefor oral administration may be prepared as discrete units such astablets, pills, troches, lozenges, aqueous or oil suspensions,dispersible powders or granules, emulsions, hard or soft capsules, e.g.gelatin capsules, syrups or elixirs. Formulations of a compound intendedfor oral use may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions.

Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above.

When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents may be added. Syrupsand elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

Sterile injectable forms of the compositions described herein (e.g. forparenteral administration) may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or di-glycerides. Fatty acids, such as oleicacid and its glyceride derivatives are useful in the preparation ofinjectables, as are natural pharmaceutically-acceptable oils, such asolive oil or castor oil, especially in their polyoxyethylated versions.These oil solutions or suspensions may also contain a long-chain alcoholdiluent or dispersant, such as carboxymethyl cellulose or similardispersing agents which are commonly used in the formulation ofpharmaceutically acceptable dosage forms including emulsions andsuspensions. Other commonly used surfactants, such as Tweens, Spans andother emulsifying agents or bioavailability enhancers which are commonlyused in the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms may also be used for the purposes of injectableformulations.

Oily suspensions may be formulated by suspending the compound of FormulaIA or Formula IB in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as butylated hydroxyanisol oralpha-tocopherol.

Aqueous suspensions of compounds of Formula IA or Formula IB contain theactive materials in admixture with excipients suitable for themanufacture of aqueous suspensions. Such excipients include a suspendingagent, such as sodium carboxymethylcellulose, croscarmellose, povidone,methylcellulose, hydroxypropyl methylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound described herein, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsulated matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

The injectable solutions or microemulsions may be introduced into apatient's bloodstream by local bolus injection. Alternatively, it may beadvantageous to administer the solution or microemulsion in such a wayas to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds describedherein with suitable non-irritating excipients or carriers such as cocoabutter, beeswax, polyethylene glycol or a suppository wax which aresolid at ambient temperature but liquid at body temperature andtherefore melt in the rectum or vaginal cavity and release the activecompound. Other formulations suitable for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprays.

The pharmaceutical compositions described herein may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the ear, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Dosage forms for topical or transdermal administration of a compounddescribed herein include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel. Topical applicationfor the lower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation.Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum. For treatment of theeye or other external tissues, e.g., mouth and skin, the formulationsmay be applied as a topical ointment or cream containing the activeingredient(s) in an amount of, for example, 0.075 to 20% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither an oil-based, paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include a polyhydric alcohol, i.e. an alcohol having two ormore hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations may desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs.

The oily phase of emulsions prepared using compounds of Formula IA orFormula IB may be constituted from known ingredients in a known manner.While the phase may comprise merely an emulsifier (otherwise known as anemulgent), it desirably comprises a mixture of at least one emulsifierwith a fat or an oil or with both a fat and an oil. A hydrophilicemulsifier may be included together with a lipophilic emulsifier whichacts as a stabilizer. In some embodiments, the emulsifier includes bothan oil and a fat. Together, the emulsifier(s) with or withoutstabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulgents and emulsion stabilizers suitable for use in the formulationof compounds of Formula IA or Formula IB include Tween™-60, Span™-80,cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glycerylmono-stearate and sodium lauryl sulfate.

The pharmaceutical compositions may also be administered by nasalaerosol or by inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other conventional solubilizing or dispersingagents. Formulations suitable for intrapulmonary or nasal administrationhave a particle size for example in the range of 0.1 to 500 micros(including particles in a range between 0.1 and 500 microns inincrements microns such as 0.5, 1, 30, 35 microns, etc) which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs.

The pharmaceutical composition (or formulation) for use may be packagedin a variety of ways depending upon the method used for administeringthe drug. Generally, an article for distribution includes a containerhaving deposited therein the pharmaceutical formulation in anappropriate form. Suitable containers are well-known to those skilled inthe art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

In another aspect, a compound of Formula IA or Formula IB or apharmaceutically acceptable salt thereof, may be formulated in aveterinary composition comprising a veterinary carrier. Veterinarycarriers are materials useful for the purpose of administering thecomposition and may be solid, liquid or gaseous materials which areotherwise inert or acceptable in the veterinary art and are compatiblewith the active ingredient. These veterinary compositions may beadministered parenterally, orally or by any other desired route.

Therapeutic Methods

The present disclosure relates to stimulators of soluble guanylatecyclase (sGC), pharmaceutical formulations thereof and their use, aloneor in combination with one or more additional agents, for treatingand/or preventing various diseases, wherein an increase in theconcentration of NO might be desirable, such as pulmonary hypertension,arterial hypertension, heart failure, atherosclerosis, inflammation,thrombosis, renal fibrosis and failure, liver cirrhosis, erectiledysfunction and other related cardiovascular disorders.

In one embodiment, the compounds herein disclosed are NO-independent,heme-dependent sGC stimulators that can be used to prevent and/or treatconditions, diseases or disorders in which it is considered desirable toincrease the concentration of cGMP. Increased concentration of cGMPleads to vasodilatation, inhibition of platelet aggregation andadhesion, anti-hypertensive effects, anti-remodeling effects,anti-apoptotic effects, anti-inflammatory effects and neuronal signaltransmission effects. Thus, sGC stimulators may be used to treat and/orprevent a range of diseases and disorders, including but not limited tocardiovascular, endothelial, pulmonary, renal, hepatic and sexualdiseases and disorders.

In other embodiments, the compounds here disclosed are sGC stimulatorsthat may be useful in the prevention and/or treatment of diseases anddisorders characterized by undesirable reduced bioavailability of and/orsensitivity to NO, such as those associated with conditions of oxidativestress or nitrosative stress.

Specific diseases of disorders which may be treated and/or prevented byadministering an sGC stimulator, include but are not limited to:arterial hypertension, pulmonary hypertension, heart failure, stroke,septic shock, atherosclerosis, thrombosis, renal fibrosis, ischemicrenal disease and renal failure, liver cirrhosis, erectile dysfunction,male and female sexual dysfunction, sickle cell anemia, asthma, chronicobstructive pulmonary disease, and neuro inflammatory diseases ordisorders.

Pulmonary hypertension (PH) is a disease characterized by sustainedelevations of blood pressure in the pulmonary vasculature (pulmonaryartery, pulmonary vein and pulmonary capillaries), which results inright heart hypertrophy, eventually leading to right heart failure anddeath. Common symptoms of PH include shortness of breath, dizziness andfainting, all of which are exacerbated by exertion. Without treatment,median life expectancy following diagnosis is 2.8 years. PH exists inmany different forms, which are categorized according to their etiology.Categories include pulmonary arterial hypertension (PAH), PH with leftheart disease, PH associated with lung diseases and/or hypoxemia, PH dueto chronic thrombotic and/or embolic disease and miscellaneous PH. PAHis rare in the general population, but the prevalence increases inassociation with certain common conditions such as HIV infection,scleroderma and sickle cell disease. Other forms of PH are generallymore common than PAH, and, for instance, the association of PH withchronic obstructive pulmonary disease (COPD) is of particular concern.Current treatment for pulmonary hypertension depends on the stage andthe mechanism of the disease.

The compounds according to Formula IA or Formula IB of the presentinvention as well as pharmaceutically acceptable salts thereof, asstimulators of sGC, are useful in the prevention and/or treatment of thefollowing types of diseases, conditions and disorders which can benefitfrom sGC stimulation:

-   -   (1) Peripheral or cardiac vascular disorders/conditions:        -   pulmonary hypertension, pulmonary arterial hypertension, and            associated pulmonary vascular remodeling (e.g. localized            thrombosis and right heart hypertrophy); pulmonary            hypertonia; primary pulmonary hypertension, secondary            pulmonary hypertension, familial pulmonary hypertension,            sporadic pulmonary hypertension, pre-capillary pulmonary            hypertension, idiopathic pulmonary hypertension, thrombotic            pulmonary arteriopathy, plexogenic pulmonary arteriopathy;            pulmonary hypertension associated with or related to: left            ventricular dysfunction, hypoxemia, mitral valve disease,            constrictive pericarditis, aortic stenosis, cardiomyopathy,            mediastinal fibrosis, pulmonary fibrosis, anomalous            pulmonary venous drainage, pulmonary venooclusive disease,            pulmonary vasculitis, collagen vascular disease, congenital            heart disease, pulmonary venous hypertension, interstitial            lung disease, sleep-disordered breathing, apnea, alveolar            hypoventilation disorders, chronic exposure to high            altitude, neonatal lung disease, alveolar-capillary            dysplasia, sickle cell disease, other coagulation disorders,            chronic thromboembolism, pulmonary embolism (due to tumor,            parasites or foreign material), connective tissue disease,            lupus, schitosomiasis, sarcoidosis, chronic obstructive            pulmonary disease, emphysema, chronic bronchitis, pulmonary            capillary hemangiomatosis; histiocytosis X,            lymphangiomatosis and compressed pulmonary vessels (such as            due to adenopathy, tumor or fibrosing mediastinitis)        -   disorders related to high blood pressure and decreased            coronary blood flow such as increased acute and chronic            coronary blood pressure, arterial hypertension and vascular            disorder resulting from cardiac and renal complications            (e.g. heart disease, stroke, cerebral ischemia, renal            failure); congestive heart failure; thromboembolic disorders            and ischemias such as myocardial infarction, stroke,            transient ischemic attacks; stable or unstable angina            pectoris; arrhythmias; diastolic dysfunction; coronary            insufficiency;        -   Atherosclerosis (e.g., associated with endothelial injury,            platelet and monocyte adhesion and aggregation, smooth            muscle proliferation and migration);    -   restenosis (e.g. developed after thrombolysis therapies,        percutaneous transluminal angioplasties (PTAs), percutaneous        transluminal coronary angioplasties (PTCAs) and bypass);        inflammation;        -   liver cirrhosis, associated with chronic liver disease,            hepatic fibrosis, hepatic stellate cell activation, hepatic            fibrous collagen and total collagen accumulation; liver            disease of necro-inflammatory and/or of immunological            origin; and    -   (2) Urogenital system disorders, such as renal fibrosis and        renal failure resulting from chronic kidney diseases or        insufficiency (e.g. due to accumulation/deposition and tissue        injury, progressive sclerosis, glomerunephritis); prostate        hypertrophy; erectile dysfunction; female sexual dysfunction and        incontinence.

In some embodiments of the invention, the compounds according to FormulaIA or Formula IB as well as pharmaceutically acceptable salts thereofare also useful in the prevention and/or treatment of the followingtypes of diseases, conditions and disorders which can benefit from sGCstimulation:

(a) A peripheral or cardiac vascular disorder or health conditionselected from: pulmonary hypertension, pulmonary arterial hypertension,and associated pulmonary vascular remodeling, localized pulmonarythrombosis, right heart hypertrophy, pulmonary hypertonia, primarypulmonary hypertension, secondary pulmonary hypertension, familialpulmonary hypertension, sporadic pulmonary hypertension, pre-capillarypulmonary hypertension, idiopathic pulmonary hypertension, thromboticpulmonary arteriopathy, plexogenic pulmonary arteriopathy; pulmonaryhypertension associated with or related to: left ventriculardysfunction, hypoxemia, mitral valve disease, constrictive pericarditis,aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonaryfibrosis, anomalous pulmonary venous drainage, pulmonary venooclusivedisease, pulmonary vasculitis, collagen vascular disease, congenitalheart disease, pulmonary venous hypertension, interstitial lung disease,sleep-disordered breathing, apnea, alveolar hypoventilation disorders,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorders, chronic thromboembolism, pulmonary embolism, connectivetissue disease, lupus, schitosomiasis, sarcoidosis, chronic obstructivepulmonary disease, emphysema, chronic bronchitis, pulmonary capillaryhemangiomatosis; histiocytosis X, lymphangiomatosis or compressedpulmonary vessels;

(b) Liver cirrhosis, or (c) a urogenital system disorder selected fromrenal fibrosis, renal failure resulting from chronic kidney diseases orinsufficiency, erectile dysfunction or female sexual dysfunction.

In other embodiments of the invention, the compounds according toFormula IA or Formula IB as well as pharmaceutically acceptable saltsthereof are useful in the prevention and/or treatment of the followingtypes of diseases, conditions and disorders which can benefit from sGCstimulation:

-   -   pulmonary hypertension, pulmonary arterial hypertension, and        associated pulmonary vascular remodeling, localized pulmonary        thrombosis, right heart hypertrophy, pulmonary hypertonia,        primary pulmonary hypertension, secondary pulmonary        hypertension, familial pulmonary hypertension, sporadic        pulmonary hypertension, pre-capillary pulmonary hypertension,        idiopathic pulmonary hypertension, thrombotic pulmonary        arteriopathy, plexogenic pulmonary arteriopathy or chronic        obstructive pulmonary disease, liver cirrhosis, renal fibrosis,        renal failure resulting from chronic kidney diseases or        insufficiency, erectile dysfunction or female sexual        dysfunction.

In still other embodiments, the compounds according to Formula IA orFormula IB as well as pharmaceutically acceptable salts thereof areuseful in the prevention and/or treatment of the following types ofdiseases, conditions and disorders which can benefit from sGCstimulation:

-   -   Pulmonary hypertension, pulmonary arterial hypertension, and        associated pulmonary vascular remodeling, pulmonary hypertonia,        primary pulmonary hypertension, secondary pulmonary        hypertension, familial pulmonary hypertension, sporadic        pulmonary hypertension, pre-capillary pulmonary hypertension or        idiopathic pulmonary hypertension.

The terms, “disease”, “disorder” and “condition” may be usedinterchangeably here to refer to a sGC, cGMP and/or NO mediated medicalor pathological condition.

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey, or a mammal),specifically a “mammal” including a non-primate (e.g., a cow, pig,horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and aprimate (e.g., a monkey, chimpanzee and a human), and more specificallya human. In some embodiments, the subject is a non-human animal such asa farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog,cat, guinea pig or rabbit). In some embodiments, the subject is a human.

The invention also provides a method for treating one of these diseases,conditions and disorders in a subject, comprising administering atherapeutically effective amount of the compound of Formula IA orFormula IB, or a pharmaceutically acceptable salt thereof, in thesubject in need of the treatment. Alternatively, the invention providesthe use of the compound of Formula IA or Formula IB, or apharmaceutically acceptable salt thereof, in the treatment of one ofthese diseases, conditions and disorders in a subject in need of thetreatment. The invention further provides a method of making amedicament useful for treating one of these diseases, conditions anddisorders comprising using the compound of Formula IA or Formula IB, ora pharmaceutically acceptable salt thereof

The term “biological sample”, as used herein, refers to an in vitro orex vivo sample, and includes, without limitation, cell cultures orextracts thereof; biopsied material obtained from a mammal or extractsthereof; blood, saliva, urine, faeces, semen, tears, lymphatic fluid,ocular fluid, vitreous humour, or other body fluids or extracts thereof

“Treat”, “treating” or “treatment” with regard to a disorder or diseaserefers to alleviating or abrogating the cause and/or the effects of thedisorder or disease. As used herein, the terms “treat”, “treatment” and“treating” refer to the reduction or amelioration of the progression,severity and/or duration of a sGC, cGMP and/or NO mediated condition, orthe amelioration of one or more symptoms (preferably, one or morediscernable symptoms) of said condition (i.e. “managing” without“curing” the condition), resulting from the administration of one ormore therapies (e.g., one or more therapeutic agents such as a compoundor composition of the invention). In specific embodiments, the terms“treat”; “treatment” and “treating” refer to the amelioration of atleast one measurable physical parameter of a sGC, cGMP and/or NOmediated condition. In other embodiments the terms “treat”, “treatment”and “treating” refer to the inhibition of the progression of a sGC, cGMPand/or NO mediated condition, either physically by, e.g., stabilizationof a discernable symptom or physiologically by, e.g., stabilization of aphysical parameter, or both.

The term “preventing” as used herein refers to administering amedicament beforehand to avert or forestall the appearance of one ormore symptoms of a disease or disorder. The person of ordinary skill inthe medical art recognizes that the term “prevent” is not an absoluteterm. In the medical art it is understood to refer to the prophylacticadministration of a drug to substantially diminish the likelihood orseriousness of a condition, or symptom of the condition and this is thesense intended in this disclosure. The Physician's Desk Reference, astandard text in the field, uses the term “prevent” hundreds of times.As used therein, the terms “prevent”, “preventing” and “prevention” withregard to a disorder or disease, refer to averting the cause, effects,symptoms or progression of a disease or disorder prior to the disease ordisorder fully manifesting itself

In one embodiment, the methods of the invention are a preventative or“pre-emptive” measure to a patient, specifically a human, having apredisposition (e.g. a genetic predisposition) to developing a sGC, cGMPand/or NO related disease, disorder or symptom.

In other embodiments, the methods of the invention are a preventative or“pre-emptive” measure to a patient, specifically a human, suffering froma disease, disorder or condition that makes him at risk of developing asGC, cGM or NO related disease, disorder or symptom.

The compounds and pharmaceutical compositions described herein can beused alone or in combination therapy for the treatment or prevention ofa disease or disorder mediated, regulated or influenced by sGC, cGMPand/or NO.

Compounds and compositions here disclosed are also useful for veterinarytreatment of companion animals, exotic animals and farm animals,including, without limitation, dogs, cats, mice, rats, hamsters,gerbils, guinea pigs, rabbits, horses, pigs and cattle.

In other embodiments, the invention provides a method of stimulating sGCactivity in a biological sample, comprising contacting said biologicalsample with a compound or composition of the invention. Use of a sGCstimulator in a biological sample is useful for a variety of purposesknown to one of skill in the art. Examples of such purposes include,without limitation, biological assays and biological specimen storage.

Combination Therapies

The compounds and pharmaceutical compositions described herein can beused in combination therapy with one or more additional therapeuticagents. For combination treatment with more than one active agent, wherethe active agents are in separate dosage formulations, the active agentsmay be administered separately or in conjunction. In addition, theadministration of one element may be prior to, concurrent to, orsubsequent to the administration of the other agent.

When co-administered with other agents, e.g., when co-administered withanother pain medication, an “effective amount” of the second agent willdepend on the type of drug used. Suitable dosages are known for approvedagents and can be adjusted by the skilled artisan according to thecondition of the subject, the type of condition(s) being treated and theamount of a compound described herein being used. In cases where noamount is expressly noted, an effective amount should be assumed. Forexample, compounds described herein can be administered to a subject ina dosage range from between about 0.01 to about 10,000 mg/kg bodyweight/day, about 0.01 to about 5000 mg/kg body weight/day, about 0.01to about 3000 mg/kg body weight/day, about 0.01 to about 1000 mg/kg bodyweight/day, about 0.01 to about 500 mg/kg body weight/day, about 0.01 toabout 300 mg/kg body weight/day, about 0.01 to about 100 mg/kg bodyweight/day.

When “combination therapy” is employed, an effective amount can beachieved using a first amount of a compound of Formula IA or Formula IBor a pharmaceutically acceptable salt thereof, and a second amount of anadditional suitable therapeutic agent.

In one embodiment of this invention, the compound of Formula IA orFormula IB and the additional therapeutic agent are each administered inan effective amount (i.e., each in an amount which would betherapeutically effective if administered alone). In another embodiment,the compound of Structural Formula IA or Formula IB and the additionaltherapeutic agent are each administered in an amount which alone doesnot provide a therapeutic effect (a sub-therapeutic dose). In yetanother embodiment, the compound of Structural Formula IA or Formula IBcan be administered in an effective amount, while the additionaltherapeutic agent is administered in a sub-therapeutic dose. In stillanother embodiment, the compound of Structural Formula IA or Formula IBcan be administered in a sub-therapeutic dose, while the additionaltherapeutic agent, for example, a suitable cancer-therapeutic agent isadministered in an effective amount.

As used herein, the terms “in combination” or “co-administration” can beused interchangeably to refer to the use of more than one therapy (e.g.,one or more prophylactic and/or therapeutic agents). The use of theterms does not restrict the order in which therapies (e.g., prophylacticand/or therapeutic agents) are administered to a subject.

Co-administration encompasses administration of the first and secondamounts of the compounds in an essentially simultaneous manner, such asin a single pharmaceutical composition, for example, capsule or tablethaving a fixed ratio of first and second amounts, or in multiple,separate capsules or tablets for each. In addition, such coadministration also encompasses use of each compound in a sequentialmanner in either order. When co-administration involves the separateadministration of the first amount of a compound of Structural FormulaeI and a second amount of an additional therapeutic agent, the compoundsare administered sufficiently close in time to have the desiredtherapeutic effect. For example, the period of time between eachadministration which can result in the desired therapeutic effect, canrange from minutes to hours and can be determined taking into accountthe properties of each compound such as potency, solubility,bioavailability, plasma half-life and kinetic profile. For example, acompound of Formula IA or Formula IB and the second therapeutic agentcan be administered in any order within about 24 hours of each other,within about 16 hours of each other, within about 8 hours of each other,within about 4 hours of each other, within about 1 hour of each other orwithin about 30 minutes of each other.

More, specifically, a first therapy (e.g., a prophylactic or therapeuticagent such as a compound described herein) can be administered prior to(e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeksbefore), concomitantly with, or subsequent to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) theadministration of a second therapy (e.g., a prophylactic or therapeuticagent such as an anti-cancer agent) to a subject.

Examples of other therapeutic agents that may be combined with acompound of this disclosure, either administered separately or in thesame pharmaceutical composition, include, but are not limited to:

-   -   (1) Endothelium-derived releasing factor (EDRF);    -   (2) NO donors such as a nitrosothiol, a nitrite, a sydnonimine,        a NONOate, a N-nitrosoamine, a N-hydroxyl nitrosamine, a        nitrosimine, nitrotyrosine, a diazetine dioxide, an oxatriazole        5-imine, an oxime, a hydroxylamine, a N-hydroxyguanidine, a        hydroxyurea or a furoxan. Some examples of these types of        compounds include: glyceryl trinitrate (also known as GTN,        nitroglycerin, nitroglycerine, and trinitroglycerin), the        nitrate ester of glycerol; sodium nitroprusside (SNP), wherein a        molecule of nitric oxide is coordinated to iron metal forming a        square bipyramidal complex; 3-morpholinosydnonimine (SIN-1), a        zwitterionic compound formed by combination of a morpholine and        a sydnonimine; S-nitroso-N-acetylpenicillamine (SNAP), an        N-acetylated amino acid derivative with a nitrosothiol        functional group; diethylenetriamine/NO (DETA/NO), a compound of        nitric oxide covalently linked to diethylenetriamine; and NCX        4016, an m-nitroxymethyl phenyl ester of acetyl salicylic acid.        More specific examples of some of these classes of NO donors        include: the classic nitrovasodilators, such as organic nitrate        and nitrite esters, including nitroglycerin, amyl nitrite,        isosorbide dinitrate, isosorbide 5-mononitrate, and nicorandil;        Isosorbide (Dilatrate®-SR, Imdur®, Ismo®, Isordil®, Titradose®,        Monoket®), FK 409 (NOR-3); FR 144420 (NOR-4);        3-morpholinosydnonimine; Linsidomine chlorohydrate (“SIN-1”);        S-nitroso-N-acetylpenicillamine (“SNAP”); AZD3582 (CINOD lead        compound), NCX 4016, NCX 701, NCX 1022, HCT 1026, NCX 1015, NCX        950, NCX 1000, NCX 1020, AZD 4717, NCX 1510/NCX 1512, NCX 2216,        and NCX 4040 (all available from NicOx S.A.),        S-nitrosoglutathione (GSNO), S-nitrosoglutathione        mono-ethyl-ester (GSNO-ester),        6-(2-hydroxy-1-methyl-nitrosohydrazino)-N-methyl-1-hexanamine        (NOC-9) or diethylamine NONOate. Nitric oxide donors are also as        disclosed in U.S. Pat. Nos. 5,155,137, 5,366,997, 5,405,919,        5,650,442, 5,700,830, 5,632,981, 6,290,981, 5,691,423 5,721,365,        5,714,511, 6,511,911, and 5,814,666, Chrysselis et al. (2002) J        Med Chem. 45:5406-9 (such as NO donors 14 and 17), and Nitric        Oxide Donors for Pharmaceutical and Biological Research, Eds:        Peng George Wang, Tingwei Bill Cai, Naoyuki Taniguchi, Wiley,        2005;    -   (3) Other substances that enhance cGMP concentrations such as        protoporphyrin IX, arachidonic acid and phenyl hydrazine        derivatives;    -   (4) Nitric Oxide Synthase substrates: for example,        n-hydroxyguanidine based analogs, such as        N[G]-hydroxy-L-arginine (NOHA),        1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine,        and PR5        (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine);        L-arginine derivatives (such as homo-Arg, homo-NOHA,        N-tert-butyloxy- and N-(3-methyl-2-butenyl)oxy-L-arginine,        canavanine, epsilon guanidine-carpoic acid, agmatine,        hydroxyl-agmatine, and L-tyrosyl-L-arginine);        N-alkyl-N′-hydroxyguanidines (such as        N-cyclopropyl-N′-hydroxyguanidine and        N-butyl-N′-hydroxyguanidine), N-aryl-N′-hydroxyguanidines (such        as N-phenyl-N′-hydroxyguanidine and its para-substituted        derivatives which bear —F, —Cl, -methyl, —OH substituents,        respectively); guanidine derivatives such as 3-(trifluormethyl)        propylguanidine; and others reviewed in Cali et al. (2005,        Current Topics in Medicinal Chemistry 5:721-736) and disclosed        in the references cited therein;    -   (5) Compounds which enhance eNOS transcription: for example        those described in WO 02/064146, WO 02/064545, WO 02/064546 and        WO 02/064565, and corresponding patent documents such as        US2003/0008915, US2003/0022935, US2003/0022939 and        US2003/0055093. Other eNOS transcriptional enhancers including        those described in US20050101599 (e.g.        2,2-difluorobenzo[1,3]dioxol-5-carboxylic acid indan-2-ylamide,        and 4-fluoro-N-(indan-2-yl)-benzamide), and Sanofi-Aventis        compounds AVE3085 and AVE9488 (CA Registry NO. 916514-70-0;        Schafer et al., Journal of Thrombosis and Homeostasis 2005;        Volume 3, Supplement 1: abstract number P1487);    -   (6) NO independent heme-independent sGC activators, including,        but not limited to:        -   BAY 58-2667 (see patent publication DE19943635)

-   -   -   HMR-1766 (ataciguat sodium, see patent publication            WO2000002851)

-   -   -   S 3448            (2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide            (see patent publications DE19830430 and WO2000002851)

-   -   -    and        -   HMR-1069 (Sanofi-Aventis).

    -   (7) Heme-dependent sGC stimulators including, but not limited        to:        -   YC-1 (see patent publications EP667345 and DE19744026)

-   -   -   BAY 41-2272 (see patent publications DE19834047 and            DE19942809)

-   -   -   BAY 41-8543 (see patent publication DE19834044)

-   -   -   BAY 63-2521 (see patent publication DE19834044)        -   CFM-1571 (see patent publication WO2000027394)

-   -   and other compounds disclosed in Tetrahedron Letters (2003),        44(48): 8661-8663.    -   (8) Compounds that inhibit the degradation of cGMP, such as:    -   PDE5 inhibitors, such as, for example, Sildenafil (Viagra®) and        other related agents such as Avanafil, Lodenafil, Mirodenafil,        Sildenafil citrate, Tadalafil (Cialis®), Vardenafil (Levitra®)        and Udenafil; Alprostadil; and    -   Dipyridamole;    -   (9) Calcium channel blockers such as:    -   Dihydropyridine calcium channel blockers: Amlodipine (Norvasc),        Aranidipine (Sapresta), Azelnidipine (Calblock), Barnidipine        (HypoCa), Benidipine (Coniel), Cilnidipine (Atelec, Cinalong,        Siscard), Clevidipine (Cleviprex), Efonidipine (Landel),        Felodipine (Plendil), Lacidipine (Motens, Lacipil),        Lercanidipine (Zanidip), Manidipine (Calslot, Madipine),        Nicardipine (Cardene, Carden SR), Nifedipine (Procardia,        Adalat), Nilvadipine (Nivadil), Nimodipine (Nimotop),        Nisoldipine (Baymycard, Sular, Syscor), Nitrendipine (Cardif,        Nitrepin, Baylotensin), Pranidipine (Acalas);    -   Phenylalkylamine calcium channel blockers: Verapamil (Calan,        Isoptin)

-   -   Gallopamil (Procorum, D600);    -   Benzothiazepines: Diltiazem (Cardizem);

-   -   Nonselective calcium channel inhibitors such as: mibefradil,        bepridil and fluspirilene, fendiline    -   (10) Endothelin receptor antagonists (ERAs): for instance the        dual (ET_(A) and ET_(B)) endothelin receptor antagonist Bosentan        (marketed as Tracleer®); Sitaxentan, marketed under the name        Thelin®; Ambrisentan is marketed as Letairis® in U.S;        dual/nonselective endothelin antagonist Actelion-1, that entered        clinical trials in 2008;    -   (11) Prostacyclin derivatives: for instance prostacyclin        (prostaglandin I₂), Epoprostenol (synthetic prostacyclin,        marketed as Flolan®); Treprostinil (Remodulin®) Iloprost        (Ilomedin®), Iloprost (marketed as Ventavis®); oral and inhaled        forms of Remodulin® that are under development; Beraprost, an        oral prostanoid available in Japan and South Korea;    -   (12) Antihyperlipidemics such as: cholestyramine, colestipol,        and colesevelam; statins such as Atorvastatin, Simvastatin,        Lovastatin and Pravastatin; Rosuvastatin; also combinations of        statins, niacin, intestinal cholesterol absorption-inhibiting        supplements (ezetimibe and others, and to a much lesser extent        fibrates);    -   (13) Anticoagulants, such as the following types:        -   Coumarines (Vitamin K antagonists): Warfarin® (Coumadin)            mostly used in the US and UK; Acenocoumarol® and            Phenprocoumon®, mainly used in other countries;            Phenindione®;        -   Heparin and derivative substances such as: Heparin; low            molecular weight heparin, Fondaparinux and Idraparinux;            -   Direct thrombin inhibitors such as: Argatroban,                Lepirudin, Bivalirudin and Dabigatran; Ximelagatran                (Exanta®), not approved in the US;        -   Tissue plasminogen activators, used to dissolve clots and            unblock arteries, such as Alteplase;    -   (14) Antiplatelet drugs: for instance thienopyridines such as        Lopidogrel and Ticlopidine; Dipyridamole; Aspirin;    -   (15) ACE inhibitors, for example the following types:        -   Sulfhydryl-containing agents such as Captopril (trade name            Capoten®), the first ACE inhibitor and Zofenopril;        -   Dicarboxylate-containing agents such as Enalapril            (Vasotec/Renitec®); Ramipril            (Altace/Tritace/Ramace/Ramiwin®); Quinapril (Accupril®)            Perindopril (Coversyl/Aceon®); Lisinopril            (Lisodur/Lopril/Novatec/Prinivil/Zestril®) and Benazepril            (Lotensin®);        -   Phosphonate-containing agents such as: Fosinopril;        -   Naturally occurring ACE inhibitors such as: Casokinins and            lactokinins, which are breakdown products of casein and whey            that occur naturally after ingestion of milk products,            especially cultured milk; The Lactotripeptides Val-Pro-Pro            and Ile-Pro-Pro produced by the probiotic Lactobacillus            helveticus or derived from casein also have ACE-inhibiting            and antihypertensive functions;    -   (16) Supplemental oxygen therapy;    -   (17) Beta blockers, such as the following types:        -   Non-selective agents: Alprenolol®, Bucindolol®, Carteolol®,            Carvedilol® (has additional α-blocking activity), Labetalol®            (has additional α-blocking activity), Nadolol®, Penbutolol®            (has intrinsic sympathomimetic activity), Pindolol® (has            intrinsic sympathomimetic activity), Propranolol® and            Timolol®;        -   β₁-Selective agents: Acebutolol® (has intrinsic            sympathomimetic activity), Atenolol®, Betaxolol®,            Bisoprolol®, Esmolol®, Metoprolol® and Nebivolol®;        -   β₂-Selective agents: Butaxamine® (weak α-adrenergic agonist            activity);    -   (18) Antiarrhythmic agents such as the following types:        -   Type I (sodium channel blockers): Quinidine, Lidocaine,            Phenytoin, Propafenone        -   Type III (potassium channel blockers): Amiodarone,            Dofetilide, Sotalol        -   Type V: Adenosine, Digoxin    -   (19) Diuretics such as: Thiazide diuretics, e.g.,        chlorothiazide, chlorthalidone, and hydrochlorothiazide; Loop        diuretics, such as furosemide; potassium-sparing diuretics such        as amiloride, spironolactone, and triamterene; combinations of        these agents;    -   (20) Exogenous vasodilators such as:        -   Adenocard®, an adenosine agonist, primarily used as an            anti-arrhythmic;        -   Alpha blockers (which block the vasoconstricting effect of            adrenaline);        -   Atrial natriuretic peptide (ANP);        -   Ethanol;        -   Histamine-inducers, which complement proteins C3a, C4a and            C5a work by triggering histamine release from mast cells and            basophil granulocytes;        -   Tetrahydrocannabinol (THC), major active chemical in            marijuana which has minor vasodilatory effects;        -   Papaverine, an alkaloid found in the opium poppy papaver            somniferum;    -   (21) Bronchodilators: there are two major types of        bronchodilator, β₂ agonists and anticholinergics, exemplified        below:        -   β₂ agonists: Salbutamol® or albuterol (common brand name:            Ventolin) and Terbutaline® are short acting β₂ agonists for            rapid relief of COPD symptoms. Long acting β₂ agonists            (LABAs) such as Salmeterol® and Formoterol®;        -   anticholinergics: Ipratropium® is the most widely prescribed            short acting anticholinergic drug. Tiotropium® is the most            commonly prescribed long-acting anticholinergic drug in            COPD;        -   Theophylline®, a bronchodilator and phosphodiesterase            inhibitor;    -   (22) Corticosteroids: such as beclomethasone,        methylprednisolone, betamethasone, prednisone, prenisolone,        triamcinolone, dexamethasone, fluticasone, flunisolide and        hydrocortisone, and corticosteroid analogs such as budesonide    -   (23) Dietary supplements such as, for example: omega-3 oils;        folid acid, niacin, zinc, copper, Korean red ginseng root,        ginkgo, pine bark, Tribulus terrestris, arginine, Avena sativa,        horny goat weed, maca root, muira puama, saw palmetto, and        Swedish flower pollen; Vitamin C, Vitamin E, Vitamin K2;        Testosterone supplements, Zoraxel, Naltrexone, Bremelanotide        (formerly PT-141), Melanotan II, hMaxi-K; Prelox: a Proprietary        mix/combination of naturally occurring ingredients, L-arginine        aspartate and Pycnogenol;    -   (24) PGD2 receptor antagonists including, but not limited to,        compounds described as having PGD2 antagonizing activity in        United States Published Applications US20020022218,        US20010051624, and US20030055077, PCT Published Applications        WO9700853, WO9825919, WO03066046, WO03066047, WO03101961,        WO03101981, WO04007451, WO0178697, WO04032848, WO03097042,        WO03097598, WO03022814, WO03022813, and WO04058164, European        Patent Applications EP945450 and EP944614, and those listed in:        Torisu et al. 2004 Bioorg Med Chem Lett 14:4557, Torisu et al.        2004 Bioorg Med Chem Lett 2004 14:4891, and Torisu et al. 2004        Bioorg & Med Chem 2004 12:4685;    -   (25) Immunosuppressants such as cyclosporine (cyclosporine A,        Sandimmune® Neoral®), tacrolimus (FK-506, Prograf®), rapamycin        (sirolimus, Rapamune®) and other FK-506 type immunosuppressants,        and mycophenolate, e.g., mycophenolate mofetil (CellCept®);    -   (26) Non-steroidal anti-asthmatics such as β2-agonists (e.g.,        terbutaline, metaproterenol, fenoterol, isoetharine, albuterol,        salmeterol, bitolterol and pirbuterol) and        β2-agonist-corticosteroid combinations (e.g.,        salmeterol-fluticasone (Advair®), formoterol-budesonid        (Symbicort®)), theophylline, cromolyn, cromolyn sodium,        nedocromil, atropine, ipratropium, ipratropium bromide,        leukotriene biosynthesis inhibitors (zileuton, BAY1005);    -   (27) Non-steroidal anti-inflammatory agents (NSAIDs) such as        propionic acid derivatives (e.g., alminoprofen, benoxaprofen,        bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,        flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen,        naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,        tiaprofenic acid and tioxaprofen), acetic acid derivatives        (e.g., indomethacin, acemetacin, alclofenac, clidanac,        diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac,        ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin,        zidometacin and zomepirac), fenamic acid derivatives (e.g.,        flufenamic acid, meclofenamic acid, mefenamic acid, niflumic        acid and tolfenamic acid), biphenylcarboxylic acid derivatives        (e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam,        piroxicam, sudoxicam and tenoxican), salicylates (e.g., acetyl        salicylic acid and sulfasalazine) and the pyrazolones (e.g.,        apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone        and phenylbutazone);    -   (28) Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib        (Celebrex®), rofecoxib (Vioxx®), valdecoxib, etoricoxib,        parecoxib and lumiracoxib; (opioid analgesics such as codeine,        fentanyl, hydromorphone, levorphanol, meperidine, methadone,        morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine,        butorphanol, dezocine, nalbuphine and pentazocine; and    -   (29) Anti-diabetic agents such as insulin and insulin mimetics,        sulfonylureas (e.g., glyburide, meglinatide), biguanides, e.g.,        metformin (Glucophage®), α-glucosidase inhibitors (acarbose),        thiazolidinone compounds, e.g., rosiglitazone (Avandia®),        troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) and        englitazone.

Kits

The compounds and pharmaceutical formulations described herein may becontained in a kit. The kit may include single or multiple doses of twoor more agents, each packaged or formulated individually, or single ormultiple doses of two or more agents packaged or formulated incombination. Thus, one or more agents can be present in first container,and the kit can optionally include one or more agents in a secondcontainer. The container or containers are placed within a package, andthe package can optionally include administration or dosageinstructions. A kit can include additional components such as syringesor other means for administering the agents as well as diluents or othermeans for formulation. Thus, the kits can comprise: a) a pharmaceuticalcomposition comprising a compound described herein and apharmaceutically acceptable carrier, vehicle or diluent; and b) acontainer or packaging. The kits may optionally comprise instructionsdescribing a method of using the pharmaceutical compositions in one ormore of the methods described herein (e.g. preventing or treating one ormore of the diseases and disorders described herein). The kit mayoptionally comprise a second pharmaceutical composition comprising oneor more additional agents described herein for co therapy use, apharmaceutically acceptable carrier, vehicle or diluent. Thepharmaceutical composition comprising the compound described herein andthe second pharmaceutical composition contained in the kit may beoptionally combined in the same pharmaceutical composition.

A kit includes a container or packaging for containing thepharmaceutical compositions and may also include divided containers suchas a divided bottle or a divided foil packet. The container can be, forexample a paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.It is feasible that more than one container can be used together in asingle package to market a single dosage form. For example, tablets maybe contained in a bottle which is in turn contained within a box.

An example of a kit is a so-called blister pack. Blister packs are wellknown in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of individual tabletsor capsules to be packed or may have the size and shape to accommodatemultiple tablets and/or capsules to be packed. Next, the tablets orcapsules are placed in the recesses accordingly and the sheet ofrelatively stiff material is sealed against the plastic foil at the faceof the foil which is opposite from the direction in which the recesseswere formed. As a result, the tablets or capsules are individuallysealed or collectively sealed, as desired, in the recesses between theplastic foil and the sheet. Preferably the strength of the sheet is suchthat the tablets or capsules can be removed from the blister pack bymanually applying pressure on the recesses whereby an opening is formedin the sheet at the place of the recess. The tablet or capsule can thenbe removed via said opening.

It may be desirable to provide written memory aid containing informationand/or instructions for the physician, pharmacist or subject regardingwhen the medication is to be taken. A “daily dose” can be a singletablet or capsule or several tablets or capsules to be taken on a givenday. When the kit contains separate compositions, a daily dose of one ormore compositions of the kit can consist of one tablet or capsule whilea daily dose of another or more compositions of the kit can consist ofseveral tablets or capsules. A kit can take the form of a dispenserdesigned to dispense the daily doses one at a time in the order of theirintended use. The dispenser can be equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter which indicates the number of dailydoses that have been dispensed. Another example of such a memory-aid isa battery-powered micro-chip memory coupled with a liquid crystalreadout, or audible reminder signal which, for example, reads out thedate that the last daily dose has been taken and/or reminds one when thenext dose is to be taken.

EXAMPLES

All references provided in the Examples are herein incorporated byreference in their entirety. As used herein, all abbreviations, symbolsand conventions are consistent with those used in the contemporaryscientific literature. See, e.g. Janet S. Dodd, ed., The ACS StyleGuide: A Manual for Authors and Editors, 2^(nd) Ed., Washington, D.C.:American Chemical Society, 1997, herein incorporated in its entirety byreference.

The products of Examples 1-3 below were prepared using General ProcedureA described above, containing the following two steps.

Step 1: Triazole Formation:

A mixture of hydrazide A (1.0 eq) and amidine B (1.0 eq) in EtOH (0.05to 0.3 M depending on solubility) in a sealed vial was heated at100-110° C. (bath temperature) and monitored by LC/MS analysis. Oncecomplete (reaction time was typically 24 h), the reaction mixture wasconcentrated, azeotroped with toluene and dried in vacuo to affordtriazole C as the hydrochloride salt. Triazole C was carried on to thealkylation step without any further purification.

Step 2: Alkylation:

Triazole C was dissolved in DMF and treated with sodium hydride (60% w/win mineral oil, 2.0 eq) and the appropriate benzyl bromide (1.5 eq). Thereaction was stirred at room temperature and monitored by LC/MSanalysis. Once complete (reaction time was typically 30 min), thereaction mixture was diluted with ethyl acetate and washed with water (4times) and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude material was purified using SiO2 chromatographyand an appropriate solvent gradient (ethyl acetate/hexanes orDCM/methanol) to afford products D and E. In all cases, the tworegioisomers were readily separable. Structural assignments were basedon ¹H NMR analysis and confirmed by observed activities in biologicalassays.

Example 1 Compounds I-8 and I-9 Step 1

To a vial charged with pyrimidine-2-carboximidamide hydrochloride (250mg, 1.576 mmol) and oxazole-2-carbohydrazide (200 mg, 1.576 mmol) wasadded EtOH (12 mL). The vial was sealed and heated at 100° C. for 23 h.The two starting materials went into solution almost immediately. Theyellow solution was cooled (a ppt formed) and concentrated. The samplewas azeotroped two times with toluene. LCMS of the major peak: m/z215.15 (M+1). This crude product was used without further purificationor characterization. The product was a yellow solid.

Step 2

To a vial charged with2-(3-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl)oxazole hydrochloride (395mg, 1.575 mmol) was added sodium hydride (157 mg, 3.94 mmol) followed byDMF (8 mL). The reaction evolved gas, became yellow, and was stirred atrt for ˜30 min. Then 1-(bromomethyl)-2-fluorobenzene (0.310 mL, 2.52mmol) was added and the reaction stirred at room temperature for 1 h.The reaction was poured into water and extracted with EtOAc (twice). Theorganic layers were washed with water and dried with MgSO₄. The crudeproduct was added to an 80 g ISCO silica gel column and was purifiedwith a gradient of 0% to 20% (CH₃CN/MeOH [7:1])/DCM.

Examination of both products, I-8 and I-9, with mass spectrometryresulted in the following peak: LCMS m/z 323.3 (M+1).

I-8: ¹H NMR (CDCl₃/400 MHz) δ 8.88 (d, 2H), 7.76 (s, 1H), 7.35 (t, 1H),7.29 (s, 1H), 7.22-7.15 (m, 1H), 7.10 (td, 1H), 7.00-6.94 (m, 2H), 6.21(s, 2H); MS m/z: 323.3 (M+1).

I-9: ¹H NMR (CDCl₃/400 MHz) δ 8.90 (d, 2H), 7.83 (d, 1H), 7.35-7.33 (m,2H), 7.26-7.20 (m, 1H), 7.09 (td, 1H), 7.05-6.98 (m, 2H), 6.19 (s, 2H);MS m/z: 323.3 (M+1).

Example 2 Compounds I-12 and I-13

To a solution of oxazole-4-carbohydrazide (228 mg, 1.794 mmol) inethanol (8.9 mL) was added picolinimidamide hydrochloride (283 mg, 1.79mmol). After heating the orange solution at 100° C. for 50 h, thesolvent was removed in vacuo and the residue was azeotroped with toluene(2×4 mL) to give 514 mg of crude material. 187 mg of the crude material(0.75 mmol) was dissolved in N,N-dimethylformamide (3.7 mL) and treatedwith sodium hydride (60% dispersion in mineral oil, 75 mg, 1.9 mmol) ina single portion at ambient temperature. After stirring for 20 min,1-(bromomethyl)-2-fluorobenzene (0.136 mL, 1.12 mmol) was added. Thesolution was stirred for an additional 45 min, at which point thesolution was poured into water (75 mL) and extracted with ethyl acetate(3×50 mL). The organics were combined, washed with water (2×50 mL) andbrine (1×50 mL), dried over magnesium sulfate, filtered, and the solventwas removed in vacuo to give the crude product as an orange oil.Purification by silica gel chromatography (10-100% ethyl acetate inhexanes) provided4-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)oxazole,I-12 (58 mg, 0.18 mmol, 24% yield over two steps) as a tan solid and4-(1-(2-fluorobenzyl)-5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)oxazole,I-13 (21 mg, 0.06 mmol, 8.7% yield over two steps) as a brown solid.

I-12: ¹H NMR (400 MHz, CDCl₃) δ 8.75-8.53 (m, 1H), 8.50 (s, 1H),8.17-8.15 (m, 1H), 7.97 (s, 1H), 7.77 (dt, 1H), 7.32-7.29 (m, 1H),7.26-7.21 (m, 1H), 7.07-6.99 (m, 3H), 6.10 (s, 2H).

I-13: ¹H NMR (400 MHz, CDCl₃) δ 8.63-8.61 (m, 1H), 8.32-8.30 (m, 1H),8.27 (s, 1H), 7.99 (s, 1H), 7.84-7.80 (m, 1H), 7.34-7.31 (m, 1H),7.23-7.17 (m, 1H), 7.10-6.97 (m, 3H), 6.23 (s, 2H).

Example 3 Compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-11, I-16, I-20,I-21, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-58, I-59,I-51, I-52, I-45, I-46 and I-54, and Intermediate-1

Compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-11, I-16, I-20, I-21,I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-58, I-59, I-51,I-52, I-45, I-46 and I-54, and Intermediate-1 were prepared,analogously, using the conditions summarized in General Scheme A andexemplified by Example 1 and Example 2.

Compound I-1

Compound I-1 was synthesized as a white solid (9.4% yield over 2 steps)following the General Procedure A using picolinohydrazide andpicolinimidamide in step 1 and 2-fluorobenzyl bromide in step 2.

I-1: ¹H NMR (400 MHz, CDCl₃) δ 8.76 (d, 1H), 8.62 (d, 1H), 8.41 (d, 1H),8.22 (d, 1H), 7.82 (ddd, 1H), 7.79 (ddd, 1H), 7.33-7.30 (m, 2H),7.22-7.16 (m, 1H), 7.09-7.00 (m, 2H), 6.97 (t, 1H), 6.29 (s, 2H) ppm.

Compound I-2

Compound I-2 was synthesized as a clear oil (20%) over 2 steps,following General Procedure A and using benzoic hydrazide and2-amidinopyridine hydrochloride in step 1 and 2-fluorobenzyl bromide instep 2.

I-2: ¹H NMR (400 MHz, CDCl₃) δ 8.76 (m, 1H), 8.22 (d, 1H), 7.80 (app.td, 1H), 7.65 (m, 2H), 7.52-7.42 (m, 3H), 7.32-7.26 (m, 2H), 7.16 (app.t, 1H), 7.12-7.04 (m, 2H), 5.59 (s, 2H) ppm. MS: [M+H]=331.

Compounds I-3 and I-20

I-3: ¹H NMR (CDCl₃/400 MHz) δ 8.92 (d, 2H), 8.85 (dd, 1H), 8.48 (dd,1H), 7.33 (td, 1H), 7.22-7.16 (m, 1H), 7.03-6.94 (m, 3H), 6.26 (s, 2H);MS m/z: 339.3 (M+1).

I-20: ¹H NMR (CDCl₃/400 MHz) δ 8.91 (dd, 2H), 8.72 (br d, 1H), 8.27 (d,1H), 7.36 (t, 1H), 7.23-7.17 (m, 1H), 7.11 (td, 1H), 7.04-6.95 (m, 2H),6.24 (s, 2H); MS m/z: 339.3 (M+1).

Compounds I-4 and I-5

I-4: ¹H NMR (CDCl₃/400 MHz) 8.86 (dd, 1H), 8.77-8.75 (m, 1H), 8.39 (dd,1H), 8.21-8.18 (m, 1H), 7.81-7.76 (m, 1H), 7.33-7.30 (m, 1H), 7.25-7.18(m, 1H), 7.06-6.97 (m, 3H), 6.20 (s, 2H); MS m/z: 338.3 (M+1).

I-5: ¹H NMR (CDCl₃/400 MHz) 8.92 (d, 1H), 8.64-8.62 (m, 1H), 8.36 (dt,1H), 8.05 (d, 1H), 7.83 (td, 1H), 7.35-7.31 (m, 1H), 7.23-7.17 (m, 1H),7.09 (td, 1H), 7.05-6.96 (m, 2H), 6.26 (s, 2H); MS m/z: 338.3 (M+1).

Compounds I-6 and I-7

I-6: First eluting product: (Rf 0.51 in 15% (CH₃CN/MeOH [7/1])/DCM)(I-6) was obtained as a white solid (124.3 mg, 24%). ¹H NMR (CDCl₃/400MHz) δ 8.74-8.73 (m, 1H), 8.23 (d, 1H), 7.84 (d, 1H), 7.78 (td, 1H),7.33-7.30 (m, 2H), 7.25-7.20 (m, 1H), 7.11 (td, 1H), 7.06-7.00 (m, 2H),6.15 (s, 2H); MS m/z: 322.3 (M+1).

I-7: Second eluting product: (Rf 0.40 in 15% (CH₃CN/MeOH [7/1])/DCM)(I-7) was obtained as a white solid (132.7 mg, 26%). ¹H NMR (CDCl₃/400MHz) δ 8.64-8.62 (m, 1H), 8.40-8.37 (m, 1H), 7.85-7.80 (m, 1H), 7.78 (t,1H), 7.36-7.32 (m, 1H), 7.32 (t, 1H), 7.23-7.17 (m 1H), 7.12-7.08 (m,1H), 7.05-6.97 (m, 2H), 6.29 (s, 2H); MS m/z: 322.3 (M+1).

Compound I-11

I-11: ¹H NMR (CDCl₃/400 MHz) δ 8.90 (d, 2H), 7.53 (dd, 1H), 7.35 (t,1H), 7.24-7.18 (m, 2H), 7.08-6.98 (m, 3H), 6.52 (dd, 1H), 6.21 (s, 2H);MS m/z: 322.3 (M+1).

Compound I-16 and Intermediate-1

I-16 and Intermediate-1 were synthesized as a white solid (49%) and anoff-white solid (39%), respectively, following General Procedure A (step2 only) and using commercially available2-(5-bromo-1H-1,2,4-triazol-3-yl)pyridine and 2-fluorobenzyl bromide.

I-16: ¹H NMR (400 MHz, CDCl₃) δ 8.73 (m, 1H), 8.11 (d, 1H), 7.79 (m,1H), 7.35-7.29 (m, 2H), 7.22 (app. t, 1H), 7.13-7.08 (m, 2H), 5.54 (s,2H) ppm. MS: [M+H]=333, 335 (bromine isotopes).

Intermediate 1: ¹H NMR (400 MHz, CDCl₃) δ 8.64 (m, 1H), 8.21 (d, 1H),7.84 (app. td, 1H), 7.36 (m, 1H), 7.25 (m, 1H), 7.14 (m, 1H), 7.06-7.01(m, 2H), 6.18 (s, 2H) ppm. MS: [M+H]=333, 335 (bromine isotopes).

Compound I-21

Compound I-21 was synthesized as a white solid (16%) over 2 steps,following General Procedure A and using cyclopropanecarbohydrazide and2-amidinopyridine hydrochloride in step 1 and 2-fluorobenzyl bromide instep 2.

I-21: ¹H NMR (400 MHz, CDCl₃) δ 8.60 (br. d, 1H), 8.07 (d, 1H), 7.73(app. td, 1H), 7.32-7.24 (m, 2H), 7.18 (app. t, 1H), 7.11-7.05 (m, 2H),5.55 (s, 2H), 1.89 (m, 1H), 1.20 (m, 2H), 1.04 (m, 2H) ppm. MS:[M+H]=295.

Compound I-24

Compound I-24 was synthesized as a clear oil (17%, over 2 steps)following General Procedure A and using cyclobutanecarbohydrazide and2-amidinopyridine hydrochloride in step 1 and 2-fluorobenzyl bromide instep 2. The other isomer was not isolated in this experiment.

I-24: ¹H NMR (400 MHz, CDCl₃) δ 8.72 (m, 1H), 8.14 (d, 1H), 7.75 (app.td, 1H), 7.29-7.23 (m, 2H), 7.10-7.02 (m, 3H), 5.38 (s, 2H), 3.59 (app.pent., 1H), 2.54 (m, 2H), 2.27 (m, 2H), 2.07-1.93 (m, 2H) ppm. MS:[M+H]=309.

Compounds I-25 and I-26

Compounds I-25 and I-26 were synthesized as white solids (26% and 16%,respectively, over 2 steps) following General Procedure A and usingthiazole-2-carboxylic acid hydrazide and 2-amidinopyridine hydrochloridein step 1 and 2-fluorobenzyl bromide in step 2.

I-25: ¹H NMR (400 MHz, CDCl₃) δ 8.64 (m, 1H), 8.39 (d, 1H), 7.96 (m,1H), 7.84 (m, 1H), 7.43 (m, 1H), 7.35 (m, 1H), 7.22 (m, 1H), 7.12 (app.t, 1H), 7.05-6.98 (m, 2H), 6.28 (s, 2H) ppm. MS: [M+H]=338.

I-26: ¹H NMR (400 MHz, CDCl₃) δ 8.77 (m, 1H), 8.21 (d, 1H), 7.95 (d,1H), 7.80 (app. td, 1H), 7.54 (d, 1H), 7.33 (m, 1H), 7.24 (m, 1H),7.14-7.00 (m, 3H), 6.24 (s, 2H) ppm. MS: [M+H]=338.

Compound I-27

Compound I-27 was synthesized as a white solid (48% over 2 steps)following General Procedure A using benzoic hydrazide and2-amidinopyrimidine hydrochloride in step 1 and 2-fluorobenzyl bromidein step 2.

I-27: ¹H NMR (400 MHz, CDCl₃) δ 8.93 (d, 2H), 7.69 (m, 2H), 7.52-7.43(m, 3H), 7.34 (app. t, 1H), 7.30 (m, 1H), 7.15-7.04 (m, 3H), 5.65 (s,2H) ppm. MS: [M+H]=332.

Compound I-28

Compound I-28 was synthesized as a clear oil (48% over 2 steps)following General Procedure A and using acetic acid hydrazide and2-amidinopyrimidine hydrochloride in step 1 and 2-fluorobenzyl bromidein step 2.

I-28: ¹H NMR (400 MHz, CDCl₃) δ 8.88 (d, 2H), 7.32-7.29 (m, 1H), 7.31(app. t, 1H), 7.23-7.19 (m, 1H), 7.10-7.07 (m, 2H), 5.48 (s, 2H), 2.54(s, 3H) ppm. MS: [M+H]=270.

Compounds I-29 and I-30

These two regioisomers, I-29 and I-30, were synthesized as a white solid(20%, I-30) and light yellow solid (26%, I-29) over 2 steps, followingGeneral Procedure A and using thiazole-2-carboxylic acid hydrazide and2-amidinopyrimidine hydrochloride in step 1 and 2-fluorobenzyl bromidein step 2.

I-29: ¹H NMR (400 MHz, CDCl₃) δ 8.92 (d, 2H), 7.96 (d, 1H), 7.45 (d,1H), 7.37 (app. t, 1H), 7.22-7.13 (m, 2H), 7.03-6.98 (m, 2H), 6.23 (s,2H) ppm. MS: [M+H]=339.

I-30: ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d, 2H), 7.95 (d, 1H), 7.55 (d,1H), 7.36 (app. t, 1H), 7.22 (m, 1H), 7.09-6.98 (m, 3H), 6.29 (s, 2H)ppm. MS: [M+H]=339.

Compounds I-31 and I-32

These regioisomers, I-31 and I-32, were synthesized as white solids (29%and 23% for I-31 and I-32, respectively, over 2 steps) following GeneralProcedure A using picolinohydrazide and 2-amidinopyrimidinehydrochloride in step 1 and 2-fluorobenzyl bromide in step 2.

I-31: ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, 2H), 8.74 (m, 1H), 8.40 (d,1H), 7.81 (app. td, 1H), 7.34 (app. t, 1H), 7.33 (m, 1H), 7.18 (m, 1H),7.08 (app. br t, 1H), 7.03-6.95 (m, 2H), 6.27 (s, 2H) ppm. MS:[M+H]=333.

I-32: ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d, 2H), 8.62 (m, 1H), 8.48 (d,1H), 7.82 (app. td, 1H), 7.35 (app. t, 1H), 7.33 (m, 1H), 7.18 (m, 1H),7.06-6.94 (m, 3H), 6.35 (s, 2H) ppm. MS: [M+H]=333.

Compounds I-58 and I-59 Step 2:

To a stirring solution of3-(3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)isoxazole hydrochloride (1 eq)in DMF was added sodium hydride (2.1 eq). After 10 minutes,1-(bromomethyl)-2-fluorobenzene (1.1 eq) was added and the reaction wasstirred overnight at room temperature. Brine was used to quench thereaction. Methylene chloride was used to extract the aqueous layer. Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated. SiO₂ chromatography yielded3-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)isoxazolein 13.5% yield as a solid and3-(1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-1H-1,2,4-triazol-5-yl)isoxazolein 15.7% yield as a solid.

I-58: ¹H NMR (400 MHz, CDCl₃) 8.72-8.74 (m, 1H), 8.51 (d, 1H), 8.14 (td,1H), 7.75 (dt, 1H), 7.28-7.31 (m, 1H), 7.19-7.24 (m, 1H), 7.13 (d, 1H),6.97-7.09 (m, 3H), 6.02 (s, 2H).

I-59: ¹H NMR (400 MHz, CDCl₃) 8.90-8.92 (m, 2H), 8.49-8.50 (m, 1H), 7.36(t, 1H), 7.17-7.24 (m, 1H), 7.08-7.12 (m, 1H), 7.06-7.07 (m, 1H),6.97-7.04 (m, 2H), 6.23 (s, 2H).

Compounds I-51 and 52 Step 2:

To a stirring solution of4-(3-(4-bromopyridin-2-yl)-1H-1,2,4-triazol-5-yl)thiazole (1 eq) in DMFwas added sodium hydride (2.1 eq). After 10 minutes,1-(bromomethyl)-2-fluorobenzene (1.1 eq) was added and the reaction wasstirred overnight at room temperature. Brine was used to quench thereaction. Methylene chloride was used to extract the aqueous layer. Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated. SiO₂ chromatography yielded4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazolein 1% yield as a solid and4-(5-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)thiazolein 1% yield as a solid.

I-51: ¹H NMR (400 MHz, CDCl₃) 8.88 (d, 1H), 8.56 (d, 1H), 8.39-8.40 (m,2H), 7.48-7.50 (m, 1H), 7.21-7.25 (m, 1H), 6.99-7.07 (m, 3H), 6.21 (s,2H).

I-52: ¹H NMR (400 MHz, CDCl₃) 8.92 (d, 1H), 8.43 (d, 1H), 8.27 (d, 1H),8.24 (s, 1H), 7.97 (dd, 1H), 7.27-7.28 (m, 1H), 7.03-7.11 (m, 3H), 6.15(s, 2H).

Compound I-54

Step 2:

To a stirring solution of4-(3-(4-bromopyridin-2-yl)-1H-1,2,4-triazol-5-yl)oxazole (1 eq) in DMFwas added sodium hydride (2.1 eq). After 10 minutes,1-(bromomethyl)-2-fluorobenzene (1.1 eq) was added and the reaction wasstirred overnight at room temperature. Brine was used to quench thereaction. Methylene chloride was used to extract the aqueous layer. Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated. SiO₂ chromatography yielded4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazoleas a solid in 1% yield.

I-54: ¹H NMR (400 MHz, CDCl₃) 8.55 (dd, 1H), 8.50 (d, 1H), 8.36 (dd,1H), 7.98 (d, 1H), 7.48 (dd, 1H), 7.22-7.28 (m, 1H), 7.00-7.14 (m, 3H),6.10 (s, 2H).

Compounds I-45 and I-46

These were synthesized (white solids, 1.5% and 2.7% respectively over 2steps) following General Procedure A using pyrimidine-2-carboximidamidehydrochloride and oxazole-4-carbohydrazide in step 1.

I-45: ¹H NMR (400 MHz, CDCl₃) 608.90 (d, 2H), 8.42 (s, 1H), 7.98 (s,1H), 7.34 (t, 1H), 7.22-7.17 (m, 1H), 7.11-7.07 (m, 1H), 7.02-6.95 (m,2H), 6.21 (s, 2H).

I-46: ¹H NMR (400 MHz, CDCl₃) 608.89 (d, 2H), 8.57 (s, 1H), 7.95 (s,1H), 7.32 (t, 1H), 7.23-7.17 (m, 1H), 7.03-6.95 (m, 3H), 6.16 (s, 2H).

Example 4 I-15, I-18, I-19, I-36, I-37, I-38, I-39, I-40, I-41, I-55,I-56, I-62 and I-63

Compounds I-15, I-18, I-19, I-36, I-37, I-38, I-39, I-40, I-41, I-55,I-56, I-62 and I-63 were synthesized following General Procedure Bdescribed above according to the following conditions.

Step 1: Amidine Formation:

Nitrile F was treated with sodium methoxide (0.5 M in methanol, 0.5 eq)at room temperature and the reaction monitored by LC/MS analysis. Oncethe starting nitrile was consumed (reaction time was typically 2-7 h),ammonium chloride (1.1 eq) was added and the reaction mixture wasstirred for 16-24 h. The reaction mixture was concentrated and dried invacuo resulting in the amidine B. In some case, the crude amidine wascollected by filtration. The crude amidine was carried on as describedin General Procedure A without any further purification to yieldproducts D and E.

Compound I-15

Compound I-15 was synthesized as a light yellow solid (33% over 3 steps)following General Procedure B and using 2-cyanothiazole in step 1. Thesubsequent steps were performed as described following General ProcedureA, using thiazole-2-carboxylic acid hydrazide and 2-fluorobenzyl bromidein the respective steps.

I-15: ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, 2H), 7.56 (d, 1H), 7.44 (d,1H), 7.26 (m, 1H), 7.16 (app. t, 1H), 7.09-7.02 (m, 2H), 6.22 (s, 2H)ppm. MS: [M+H]=344.

Compounds I-18 and I-19

Compounds I-19 and I-18 were synthesized as white solids (13% and 8%,respectively, over 3 steps) following General Procedure B and using6-bromopicolinonitrile in step 1. The subsequent steps were performed asdescribed following General Procedure A using thiazole-2-carboxylic acidhydrazide and 2-fluorobenzyl bromide in the respective steps.

I-18: ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, 1H), 7.97 (d, 1H), 7.70 (app.t, 1H), 7.53 (d, 1H), 7.44 (d, 1H), 7.24 (m, 1H), 7.16 (app. t, 1H),7.08-7.00 (m, 2H), 6.20 (s, 2H) ppm. MS: [M+H]=416, 418 (bromineisotopes).

I-19: ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, 1H), 7.95 (m, 1H), 7.65 (app.t, 1H), 7.54 (m, 2H), 7.25 (m, 1H), 7.11-7.00 (m, 3H), 6.24 (s, 2H) ppm.MS: [M+H]=416, 418 (bromine isotopes).

Compounds I-36 and I-37

These compounds were synthesized (white solids, 33% and 24% yields,respectively, over 3 steps) following General Procedure B and using4-bromopicolinonitrile in step 1. The subsequent steps were performed asdescribed following General Procedure A using thiazole-2-carboxylic acidhydrazide and 2-fluorobenzyl bromide in the respective steps.

I-36: ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, 1H), 8.40 (d, 1H), 7.96 (d,1H), 7.55 (d, 1H), 7.51 (dd, 1H), 7.26 (m, 1H), 7.14-7.01 (m, 3H), 6.24(s, 2H) ppm. MS: [M+H]=416, 418 (bromine isotopes).

I-37: ¹H NMR (400 MHz, CDCl₃) δ 8.64 (d, 1H), 8.45 (d, 1H), 7.98 (d,1H), 7.52 (dd, 1H), 7.45 (d, 1H), 7.23 (m, 1H), 7.12-6.99 (m, 3H), 6.25(s, 2H) ppm. MS: [M+H]=416, 418 (bromine isotopes).

Compounds I-38 and I-39

These compounds were synthesized (white solids, 22% and 20% respectivelyover 3 steps) following General Procedure B using5-fluoropicolinonitrile in step 1. The subsequent steps were performedas described following General Procedure A using thiazole-2-carboxylicacid hydrazide and 2-fluorobenzyl bromide in the respective steps.

I-38: ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, 1H), 8.23 (dd, 1H), 7.96 (d,1H), 7.54 (d, 1H), 7.51 (app. td, 1H), 7.25 (m, 1H), 7.14-7.00 (m, 3H),6.23 (s, 2H) ppm. MS: [M+H]=356.

I-39: ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, 1H), 8.45 (dd, 1H), 7.97 (d,1H), 7.55 (app. td, 1H), 7.44 (d, 1H), 7.23 (m, 1H), 7.12-6.98 (m, 3H),6.21 (s, 2H) ppm. MS: [M+H]=356.

Compounds I-40 and I-41

These compounds were synthesized (off-white solids, 11% and 30%respectively over 3 steps) following General Procedure B using2-cyanothiazole in step 1. The subsequent steps were performed asdescribed following General Procedure A using thiazole-4-carboxylic acidhydrazide and 2-fluorobenzyl bromide in the respective steps.

I-40: ¹H NMR (400 MHz, CDCl₃) δ 8.92 (d, 1H), 8.07 (d, 1H), 7.95 (d,1H), 7.54 (d, 1H), 7.24 (m, 1H), 7.13 (app. t, 1H), 7.08-7.00 (m, 2H),6.21 (s, 2H) ppm. MS: [M+H]=344.

I-41: ¹H NMR (400 MHz, CDCl₃) δ 8.89 (d, 1H), 8.39 (d, 1H), 7.96 (d,1H), 7.43 (d, 1H), 7.24 (m, 1H), 7.12-6.89 (m, 3H), 6.19 (s, 2H) ppm.MS: [M+H]=344.

Compounds I-55 and I-56

These compounds were synthesized (off-white solids, 14% and 38%respectively over 3 steps) following General Procedure B usingpyrazine-2-carbonitrile in step 1. The subsequent steps were performedas described following General Procedure A using thiazole-4-carboxylicacid hydrazide and 2-fluorobenzyl bromide in the respective steps.

I-55: ¹H NMR (400 MHz, CDCl₃) δ 9.61 (d, 1H), 8.95 (d, 1H), 8.64 (d,1H), 8.60 (dd, 1H), 8.10 (d, 1H), 7.23 (m, 1H), 7.12-6.98 (m, 3H), 6.19(s, 2H) ppm. MS: [M+H]=339.

I-56: ¹H NMR (400 MHz, CDCl₃) δ 9.44 (d, 1H), 8.90 (d, 1H), 8.70 (dd,1H), 8.61 (d, 1H), 8.41 (d, 1H), 7.25 (m, 1H), 7.11-7.00 (m, 3H), 6.23(s, 2H) ppm. MS: [M+H]=339.

Compounds I-62 and I-63

These compounds were synthesized (tan solid, 3% and white solid, 5%respectively over 3 steps) following General Procedure B usingoxazole-4-carbonitrile in step 1. The subsequent steps were performed asdescribed following General Procedure A using thiazole-2-carboxylic acidhydrazide and 2-fluorobenzyl bromide in the respective steps.

I-62: ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 7.99 (s, 1H), 7.95 (d,1H), 7.53 (d, 1H), 7.25 (m, 1H), 7.12 (app. t, 1H), 7.08-7.00 (m, 2H),6.19 (s, 2H) ppm. MS: [M+H]=328.

I-63: ¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 7.99 (s, 1H), 7.95 (d,1H), 7.42 (d, 1H), 7.26 (m, 1H), 7.13-7.02 (m, 3H), 6.09 (s, 2H) ppm.MS: [M+H]=328.

Example 5 Compound I-23

This compound was prepared according to General Procedure C.

A solution of2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16), inDMA was treated with a large excess of azetidine (˜30 eq). The resultantsolution was warmed to 100° C. and stirred at that temperature for 18 h.The reaction solution was cooled to rt, poured into 1N NaOH solution andthen extracted with EtOAc. The organic phases were dried over Na₂SO₄,filtered and conc. The crude product was purified using SiO2chromatography and an appropriate gradient (MeOH—CH₃CN (1:7)/CH₂Cl₂) togive2-(5-(azetidin-1-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine,I-23, as a white solid (88% yield).

I-23: ¹H NMR (400 MHz, CDCl₃) δ 8.70 (m, 1H), 8.06 (m, 1H), 7.73 (m,1H), 7.29-7.23 (m, 2H), 7.16-7.03 (m, 3H), 5.26 (s, 2H), 4.13 (t, 4H),2.34 (pent., 2H) ppm. MS: [M+H]=310.

Example 6 Compounds I-10, I-17, I-67, I-49 and I-50

Compounds I-10, I-17, I-67, I-49 and I-50 were prepared with GeneralProcedure D.

Compound I-10

A solution of pyrazole (1.1 eq) in DMF was treated with sodium hydride(60% w/w in mineral oil, 1.2 eq) and stirred for 10 min at roomtemperature.2-(5-Bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16, 1.0eq) was then added. The resultant mixture was warmed to 50° C. andstirred at that temperature for 1 h. The reaction solution was cooled tort, poured into water, and filtered to give2-(1-(2-fluorobenzyl)-5-(1H-pyrazol-1-yl)-1H-1,2,4-triazol-3-yl)pyridine,I-10, as a white solid (84% yield).

I-10: ¹H NMR (400 MHz, CDCl₃) δ 8.76 (br. d, 1H), 8.43 (d, 1H), 8.15 (d,1H), 7.79 (app. td, 1H), 7.77 (br. s, 1H), 7.33 (m, 1H), 7.24 (m, 1H),7.14 (app. t, 1H), 7.06-7.01 (m, 2H), 6.50 (m, 1H), 6.07 (s, 2H) ppm.MS: [M+H]=321.

Compound I-17

Compound I-17 was synthesized as an off-white solid (12% yield) from2-(3-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)pyridine(Intermediate 1). In this experiment, the temperature was raised to 140°C. and additional equivalents of pyrazole and sodium hydride were addedduring the reaction.

I-17: ¹H NMR (400 MHz, CDCl₃) δ 8.65 (br. d, 1H), 8.34 (d, 1H), 8.28 (d,1H), 7.85 (app. td, 1H), 7.78 (m, 1H), 7.36 (m, 1H), 7.23 (m, 1H), 7.17(app. t, 1H), 7.06-7.00 (m, 2H), 6.46 (m, 1H), 6.23 (s, 2H) ppm. MS:[M+H]=321.

Compound I-67 (A+B mixture)

1,2,3-triazole (1.8 eq) was stirred in a vial in DMF. Sodium hydride(2.5 eq) was added and this mixture was stirred for 20 minutes.2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16) wasadded and the reaction mixture was stirred at 100° C. for 12 hr. Brinewas poured into the reaction mixture. The aqueous layer was extractedwith ethyl acetate, dried over sodium sulfate and concentrated. Twoisomers were generated, which were purified together by SiO₂chromatography. Both isomers were characterized as2-(1-(2-fluorobenzyl)-5-(1H-1,2,3-triazol-1-yl)-1H-1,2,4-triazol-3-yl)pyridineand2-(1-(2-fluorobenzyl)-5-(2H-1,2,3-triazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridinein 47.1% yield. They seem to be present in a 3:1 mixture although it isdifficult to tell which compound is in the majority.

I-67 (A+B): ¹H NMR (400 MHz, CDCl₃) 8.75-8.78 (m, 1H), 8.5 (d, 0.3H),8.26-8.28 (m, 1H), 8.14-8.16 (m, 0.3H), 7.88 (d, 0.3H), 7.8-7.84 (m,1.3H), 7.34-7.39 (m, 1.3H), 7.15-7.24 (m, 2H), 6.99-7.08 (m, 2.5H), 6.02(s, 1H), 5.97 (s, 2H).

Compound I-49

To a stirring suspension of imidazole (1.2 eq) in DMF was added sodiumhydride (2 eq). The reaction generated gas and was stirred for 10minutes. Then2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16) wasadded. The reaction was stirred at 100° C. for 12 hr. The reaction wasquenched with brine, extracted with methylene chloride, dried oversodium sulfate and concentrated. The mixture was purified by SiO₂chromatography to afford2-(1-(2-fluorobenzyl)-5-(1H-imidazol-1-yl)-1H-1,2,4-triazol-3-yl)pyridineas a solid in 26.7% yield.

I-49: ¹H NMR (400 MHz, CDCl₃) 8.75-8.77 (m, 1H), 8.13-8.16 (m, 1H), 7.90(s, 1H), 7.82 (dt, 1H), 7.31-7.38 (m, 2H), 7.28-7.29 (m, 1H), 7.23-7.24(m, 1H), 7.18-7.20 (m, 1H), 7.07-7.15 (m, 2H), 5.50 (s, 2H).

Compound I-50

To a stirring suspension of 1,2,3-triazole (1.8 eq) in DMF was addedsodium hydride (2.5 eq). The reaction generated gas and was stirred for10 minutes. Then2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16) wasadded. The reaction was stirred at 100° C. for 12 hr. The reaction wasquenched with brine, extracted with methylene chloride, dried oversodium sulfate and concentrated. The mixture was purified by SiO₂chromatography to afford2′-(2-fluorobenzyl)-5′-(pyridin-2-yl)-2′H-1,3′-bi(1′,2′,4-triazole) in17.3% yield.

I-50: ¹H NMR (400 MHz, CDCl₃) 9.05 (s, 1H), 8.76 (d, 1H), 8.17 (s, 1H),8.14 (d, 1H), 7.81 (dt, 1H), 7.34-7.37 (m, 1H), 7.24-7.30 (m, 1H),7.16-7.20 (m, 1H), 7.02-7.07 (m, 2H), 5.98 (s, 2H).

Example 7 Compounds I-33 and I-34

Compounds I-33 and I-34 were prepared in accordance with GeneralProcedure E.

Compound I-33

To a solution of2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16, 0.95g, 2.9 mmol) in N,N-dimethylformamide (9.5 mL) was added potassiumcyanide (0.928 g, 14.3 mmol). After heating the solution at 100° C. for22 h, the solution was diluted with ethyl acetate (125 mL) and water(100 mL). The layers were separated, and the aqueous layer was extractedwith ethyl acetate (2×50 mL). The organics were combined, washed withwater (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered,and the solvent was removed in vacuo to give the crude product as anorange oil. Purification by silica gel chromatography (0-15% ethylacetate in dichloromethane) gave1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile,I-33 (250 mg, 0.90 mmol, 31% yield) as a white solid.

I-33: ¹H NMR (400 MHz, CDCl₃) δ 8.67-8.65 (m, 1H), 8.06-8.03 (m, 1H),7.73 (dt, 1H), 7.37-7.27 (m, 3H), 7.12-7.02 (m, 2H), 5.60 (s, 2H).

Compound I-34

To a solution of1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile(I-33, 100 mg, 0.358 mmol) and potassium carbonate (198 mg, 1.43 mmol)in methanol (3.6 mL) was added hydroxylamine hydrochloride (75 mg, 1.1mmol). The solution was heated at 70° C. for 1.25 h, at which point thesolution was diluted with ethyl acetate (20 mL) and the solids werefiltered off through a cotton plug. The solvent was removed in vacuo andthe crude residue was diluted with water (50 mL) and a 5:1 mixture ofdichloromethane and 2-propanol (50 mL). The layers were separated andthe organic layer was washed with water (50 mL), dried over magnesiumsulfate, and the solvent was removed in vacuo. To the resulting crude1-(2-fluorobenzyl)-N′-hydroxy-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboximidamidewas added trimethyl orthorfomate (4.5 mL, 41 mmol) and a catalyticamount of p-toluensulfonic acid monohydrate (3.4 mg, 0.018 mmol). Thesolution was heated at 100° C. for 1.5 h, and the excess orthoformatewas removed in vacuo to give the crude product as a dull yellow solid.Purification by silica gel chromatography (20-80% ethyl acetate inhexanes) gave3-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,2,4-oxadiazole,I-34 (52 mg, 0.16 mmol, 46% yield over 2 steps) as a white solid.

I-34: ¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 8.73-8.72 (m, 1H),8.29-8.27 (m, 1H), 7.79 (dt, 1H), 7.34-7.31 (m, 1H), 7.26-7.20 (m, 1H),7.12-7.08 (m, 1H), 7.03-6.99 (m, 2H), 6.05 (s, 2H).

Example 8 I-14, I-22, I-44, I-47, I-64, I-65, I-66, I-53, I-68

Compounds I-14, I-22, I-44, I-47, I-64, I-65, I-66, I-53, I-68 wereprepared with General Procedure F.

Compound I-14

To a suspension of2-(3-(6-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole(I-19) and copper(I) oxide (0.2 eq) in ethylene glycol-dioxane (4:1) ina sealed tube was added ammonium hydroxide solution (˜29% in water, ˜30eq). The resultant mixture was warmed to 100° C. and stirred at thattemperature for 24 h. The reaction solution was cooled to rt, pouredinto 1N NaOH solution and then extracted with EtOAc. The organic phaseswere dried over Na₂SO₄, filtered and conc. The crude product waspurified using SiO2 chromatography and an appropriate gradient(EtOAc/hexanes) to give6-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-2-amineas a white solid (I-14, 69% yield).

I-14: ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, 1H), 7.59 (d, 1H), 7.55 (app.t, 1H), 7.14 (d, 1H), 7.22 (m, 1H), 7.07-6.98 (m, 3H), 6.56 (d, 1H),6.22 (s, 2H), 4.74 (br. s, 2H) ppm. MS: [M+H]=353.

Compound I-22

Compound I-22 was synthesized following General Procedure F as a whitesolid (81% yield) from2-(5-(6-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)thiazole(I-18).

I-22: ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, 1H), 7.73 (d, 1H), 7.54 (app.t, 1H), 7.43 (d, 1H), 7.22 (m, 1H), 7.14 (m, 1H), 7.09-6.99 (m, 2H),6.52 (d, 1H), 6.19 (s, 2H), 4.50 (br. s, 2H) ppm. MS: [M+H]=353.

Compound I-44

This compound was synthesized as a pale green solid (73% yield) from24344-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole(I-36).

¹H NMR (400 MHz, CDCl₃) δ 8.37 (m, 1H), 7.93 (d, 1H), 7.52 (d, 1H), 7.47(m, 1H), 7.23 (m, 1H), 7.13-6.98 (m, 3H), 6.56 (m, 1H), 6.22 (s, 2H),4.24 (br. s, 2H) ppm. MS: [M+H]=353.

Compound I-47

This was synthesized as a white solid (81% yield) from2-(5-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)thiazole(I-37).

I-47: ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, 1H), 7.95 (d, 1H), 7.65 (d,1H), 7.41 (d, 1H), 7.21 (m, 1H), 7.11 (app. t, 1H), 7.06-6.98 (m, 2H),6.56 (dd, 1H), 6.29 (s, 2H), 4.28 (br. s, 2H) ppm. MS: [M+H]=353.

Compound I-64

To a stirring suspension of2-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole(I-36, 1 equiv) in ethylene glycol-dioxane (approx. 4:1) in a sealedtube was added copper(I) cyanide (3 equiv). The resultant reactionmixture was heated at 100° C. for 24 hr and then cooled to roomtemperature, treated with brine and extracted with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, concentrated andpurified using SiO₂ chromatography (ethyl acetate/hexanes) to afford2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)isonicotinamideas a solid in 11% yield.

I-64: ¹H NMR (400 MHz, CDCl₃) 8.91 (d, 1H), 8.44 (s, 1H), 7.96 (d, 1H),7.56 (d, 1H), 7.53-7.55 (m, 1H), 7.03-7.13 (m, 3H), 6.23 (s, 2H).

Compound I-65

To a stirring suspension of2-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole(I-36, 1 eq) and copper(I) oxide (1 eq) in ethylene glycol-dioxane(approx. 4:1) in a sealed tube is added morpholine (30 eq). Theresultant reaction mixture was heated at 100° C. for 12 hr. The reactionwas cooled to room temperature and treated with brine and then extractedwith ethyl acetate. The combined organic layers were dried over sodiumsulfate, concentrated and purified using SiO2 chromatography (methylenechloride/acetonitrile/methanol) to afford4-(2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-yl)morpholineas a solid in 79% yield.

I-65: ¹H NMR (400 MHz, CDCl₃) 8.42 (d, 1H), 7.90 (d, 1H), 7.59 (d, 1H),7.49 (d, 1H), 7.17-7.23 (m, 1H), 6.95-7.05 (m, 3H), 6.66-6.69 (m, 1H),6.19 (s, 2H), 3.82-3.85 (m, 4H), 3.36-3.39 (m, 4H).

Compound I-66

To a stirring suspension of4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazole(I-54, 1 eq) and copper(I) oxide (0.2 eq) in ethylene glycol-dioxane(approx. 4:1) in a sealed tube was added ammonium hydroxide (30 eq). Theresultant reaction mixture was heated at 100° C. for 12 hr. The reactionwas cooled to room temperature and treated with brine and extracted withethyl acetate. The combined organic layers were dried over sodiumsulfate, concentrated and purified using SiO2 chromatography(DCM/CAN/MeOH) to afford2-(1-(2-fluorobenzyl)-5-(oxazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-aminein 41.2% yield.

I-66: ¹H NMR (400 MHz, CDCl₃) 8.47 (d, 1H), 8.34 (d, 1H), 7.96 (d, 1H),7.42 (d, 1H), 7.20-7.24 (m, 1H), 6.98-7.10 (m, 3H), 6.55 (dd, 1H), 6.06(s, 2H).

Compound I-68

To a stirring suspension of4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazole(I-54, 1 eq) and copper(I) oxide (1 eq) in ethylene glycol-dioxane(approx. 4:1) in a sealed tube was added morpholine (30 eq). Theresultant reaction mixture was heated at 100° C. for 12 hr and thencooled to room temperature, treated with brine and extracted with ethylacetate. The combined organic layers were dried over sodium sulfate,concentrated and purified using SiO₂ chromatography (methylenechloride/acetonitrile/methanol) to afford4-(2-(1-(2-fluorobenzyl)-5-(oxazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-yl)morpholinein 10.3% yield.

I-68: ¹H NMR (400 MHz, CDCl₃) 8.51 (d, 1H), 8.47 (d, 1H), 7.96 (d, 1H),7.58 (d, 1H), 7.21-7.25 (m, 1H), 7.00-7.07 (m, 3H), 6.71-6.74 (m, 1H),6.08 (s, 2H), 3.85-3.87 (m, 4H), 3.42-3.45 (m, 4H).

Compound I-53

To a stirring suspension of4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole(I-51, 1 eq) and copper(I) oxide (1 eq) in ethylene glycol-dioxane(approx. 4:1) in a sealed tube was added ammonium hydroxide. Theresultant reaction mixture was heated at 100° C. for 12 h and thencooled to room temperature, treated with brine and extracted with ethylacetate. The combined organic layers were dried over sodium sulfate,concentrated and purified using SiO2 chromatography (methylenechloride/acetonitrile/methanol) to afford2-(1-(2-fluorobenzyl)-5-(thiazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-amineas a solid in 59.6% yield.

I-53: ¹H NMR (400 MHz, CDCl₃) 8.87 (s, 1H), 8.38 (s, 1H), 8.34 (d, 1H),7.46 (s, 1H), 7.23-7.25 (m, 1H), 7.01-7.06 (m, 3H), 6.63 (d, 1H), 6.18(s, 2H), 4.69 (br. s, 2H).

Example 9

The following compounds were prepared as described in each case.

Compounds I-43 and I-48 and Intermediates 2, 3, 4, 5 and 6 Step 1:

A suspension of thiazole-2-carbohydrazide (4.2 mmol), ethyl2-amino-2-thioxoacetate (1 equiv) and ammonium chloride (6 equiv) inethanol (150 mL) was placed in a sealed tube and this was warmed to 110°C. and stirred at that temperature for 11 days. The reaction solutionwas cooled to rt and conc. Brine was added and the mixture was adjustedto pH-6 and extracted with EtOAc. The organic phases were dried overNa₂SO₄, filtered and conc. The crude product was purified using SiO2chromatography and an appropriate solvent gradient (CH₃CN/MeOH/CH₂C₁₂)to give ethyl 3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate as anoff-white solid (Intermediate-2, 37% yield).

Step 2:

To a solution of ethyl 3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate(Intermediate-2, 1.7 mmol) in DMF (8 mL) was added sodium hydride (1.2equiv). After 10 min, 1-(bromomethyl)-2-fluorobenzene (1.2 equiv) wasadded. The reaction was stirred at ambient temperature for 35 min. Thereaction mixture was poured into water and extracted with EtOAc. Theorganic phases were washed with water and brine, dried over Na₂SO₄,filtered and conc. The crude product was purified using SiO2chromatography and an appropriate solvent gradient (EtOAc/hexanes) togive ethyl1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxylate(48%) and ethyl1-(2-fluorobenzyl)-3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate aswhite solids (44% yield).

Intermediate-3: Ethyl1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxylate ¹HNMR (400 MHz, CDCl₃) δ 7.96 (d, 1H), 7.57 (d, 1H), 7.25 (m, 1H),7.10-7.00 (m, 3H), 6.22 (s, 2H), 4.51 (q, 2H), 1.45 (t, 3H) ppm. MS:[M+H]=333.

I-43: Ethyl1-(2-fluorobenzyl)-3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate ¹HNMR (400 MHz, CDCl₃) δ 7.96 (d, 1H), 7.46 (d, 1H), 7.29 (m, 1H), 7.19(app. t, 1H), 7.11-7.05 (m, 2H), 5.97 (s, 2H), 4.49 (q, 2H), 1.43 (t,3H) ppm. MS: [M+H]=333.

Step 3:

A solution of ethyl1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxylate(Intermediate-3, 0.78 mmol) and sodium cyanide (0.1 equiv) inammonia/MeOH (7N, 30 equiv, 3.4 mL) in a seal tube was heated at 90° C.for 24 h. The reaction mixture was cooled to room temperature, conc. anddried in vacuo to afford1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxamide as atan solid (>99% yield).

Step 4:

A solution of1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxamide(Intermediate-4, 0.86 mmol) in pyridine (3.0 mL) at 0° C. was treatedwith trifluoroacetic anhydride (2 equiv) dropwise over the course of 5min. The reaction was then warmed to ambient temperature and stirred for2 h. The reaction mixture was poured into saturated NaHCO₃ solution andextracted with CH₂C₁₂. The organic phases were dried over MgSO₄,filtered and conc. The crude product was purified using SiO2chromatography and an appropriate solvent gradient (EtOAc/hexanes) togive1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carbonitrile aswhite solid (88% yield).

Step 5:

To 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carbonitrile(Intermediate-5, 0.74 mmol) was added sodium methoxide/MeOH (0.5M, 4equiv, 5.9 mL). After stirring at ambient temperature for 3 h,additional portion of sodium methoxide/MeOH (1 equiv) was added. After 2h, ammonium chloride (10 equiv) was added and the resultant mixture wasstirred at ambient for 17 h. The reaction mixture was conc.Half-saturated NaHCO₃/1N NaOH solution (10:1) was added and the aqueousmixture was extracted with EtOAc. The organic phases were dried overNa₂SO₄, filtered and conc. to afford1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboximidamideas a white solid (>99% yield).

Step 6:

To1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboximidamide(Intermediate-6, 0.33 mmol) was added a stock solution of3-ethoxyacrylonitrile (3 equiv) and DBU (1 equiv) in pyridine (3 mL).The reaction was warmed to 110° C. and stirred for 46 h. The reactionmixture was conc. and purified using SiO2 chromatography and anappropriate gradient (CH₃CN/MeOH/CH₂C₁₂) to afford2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4-amine(I-48) as a light tan solid (78% yield).

I-48: ¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (d, 1H), 8.13 (d, 1H), 8.08 (d,1H), 7.38 (m, 1H), 7.27-7.14 (m, 3H), 7.13 (br. s, 2H), 6.44 (d, 1H),6.16 (s, 2H) ppm. MS: [M+H]=354.

Compound I-57 and Intermediate-7 Step 1:

A suspension of1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboximidamide(Intermediate-6, 0.38 mmol) and 2-(phenyldiazenyl)malononitrile (1equiv) in ethanol (6 mL) in a sealed tube was heated at 110° C. for 2 h.The reaction was conc. to afford2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamineas an orange solid (>99% yield).

Step 2:

To a solution of2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine(Intermediate-7, 0.38 mmol) in DMF (2.5 mL) was added sodium hydroxidesolution (2N, 3 equiv) and sodium dithionite (5.5 equiv). The reactionwas heated to 150° C. and stirred for 2 h. The reaction mixture wasdiluted with CH₂C₁₂ and filtered. The filtrate was conc. and purifiedusing SiO2 chromatography and an appropriate gradient(CH₃CN/MeOH/CH₂C₁₂) to afford2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4,5,6-triamineas a tan solid (89% yield).

I-57: ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (d, 1H), 8.04 (d, 1H), 7.36 (m,1H), 7.23 (m, 1H), 7.16 (m, 2H), 6.11 (s, 2H), 5.83 (br. s, 4H), 4.10(br. s, 2H) ppm. MS: [M+H]=384.

Compound I-60

To a suspension of2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4,5,6-triamine(I-57, 0.31 mmol) in pyridine (2.0 mL) at 0° C. was treated with methylchloroformate (1 equiv). After 30 min, additional portions of methylchloroformate (3 equiv) were added and the reaction was stirred for 3 h.The reaction mixture was poured into water and the resultant tan solidwas collected by filtration to afford methyl4,6-diamino-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-5-ylcarbamate(74% yield).

I-60: ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (d, 1H), 8.06 (d, 1H), 7.98 (br.s, 1H), 7.37 (m, 1H), 7.23 (m, 1H), 7.16 (m, 2H), 6.22 (br. s, 4H), 6.14(s, 2H), 3.60 (s, 3H) ppm. MS: [M+H]=442.

Compound I-61

A suspension of methyl4,6-diamino-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-5-ylcarbamate(I-60, 0.16 mmol) in DMF (3.0 mL) at 0° C. was treated with sodiumhydride (1.1 equiv). After 15 min, the reaction mixture was warmed toambient temperature and stirred for 15 min. The reaction was cooled to0° C. and iodomethane (1.1 equiv) was added. The resultant mixture wasbrought to ambient temperature and stirred for 20 min. Water was addedand the aqueous mixture was extracted with EtOAc and iPrOH/CH₂C₁₂ (1:4).The organic phases were dried over Na₂SO₄, filtered, conc. and purifiedusing SiO2 chromatography and an appropriate gradient(CH₃CN/MeOH/CH₂C₁₂) to afford methyl4,6-diamino-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-5-yl(methyl)carbamateas an off-white solid (81% yield).

I-61: ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (d, 1H), 8.05 (d, 1H), 7.37 (m,1H), 7.23 (m, 1H), 7.15 (m, 2H), 6.43 (br. s, 4H), 6.14 (s, 2H), 3.64(s, 0.3 of 3H, rotamer), 3.52 (s, 0.7 of 3H, rotamer), 2.97 (s, 3H) ppm.MS: [M+H]=456.

Compound I-35

To a solution of1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile(I-33, 120 mg, 0.430 mmol) in methanol (2.0 mL) was added cesiumcarbonate (280 mg, 0.859 mmol). After stirring at room temperature for3.75 h, aqueous 0.1 N hydrochloric acid (10 mL) was added, followed byaqueous 1 N hydrochloric acid (˜1 mL) until pH˜3. After stirring for 45min, the methanol was removed in vacuo, and the crude residue wasbrought up in ethyl acetate (75 mL) and saturated aqueous sodiumbicarbonate (50 mL). The layers were separated, and the aqueous layerwas extracted with ethyl acetate (2×50 mL). The organics were washedwith brine (50 mL), dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo to give the crude product as white solid.Purification by silica gel chromatography (20-80% ethyl acetate inhexanes) gave methyl1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate (99%yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.76-8.74 (m, 1H), 8.22 (d, 1H), 7.80 (dt,1H), 7.36-7.33 (m, 1H), 7.31-7.25 (m, 1H), 7.16-7.05 (m, 3H), 6.00 (s,2H), 4.02 (s, 3H).

Compound I-42

To a solution of methyl1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate I-35(115 mg, 0.368 mmol) in methanol (2 mL) was added hydrazine hydrate (72μL, 1.5 mmol). The solution was heated to 70° C. for 3.5 h, at whichpoint the solvent was removed in vacuo to give1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbohydrazide Cas a white solid. To the crude solid (17 mg, 0.054 mmol) suspended inethyl acetate (600 μL) was added acetic formic anhydride (0.03 mL, takenfrom a 2:1 (molar ratio) of formic acid to acetic anhydride, allowed toage 2 h prior to addition). After stirring for 1.25 h, the solution wasdiluted with ethyl acetate (50 mL) and water (50 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×50mL). The organics were dried over MgSO₄, filtered, and the solvent wasremoved in vacuo to give the crude intermediate D that was carried onwithout further purification. To the crude solid was added phosphorylchloride (237 μl, 2.54 mmol) and the solution was heated to 60° C. for6.5 h. The solution was diluted with ethyl acetate (75 mL) and saturatedaqueous sodium bicarbonate (75 mL).

The layers were separated, and the aqueous layer was extracted withethyl acetate (2×50 mL). The organics were washed with brine (50 mL),dried over magnesium sulfate, filtered, and the solvent was removed invacuo. Purification by silica gel chromatography (20-95% ethyl acetatein hexanes) gave2-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,3,4-oxadiazoleI-42 (7.5 mg, 0.023 mmol, 42% yield for three steps) as a white solid.

I-42: ¹H NMR (400 MHz, CDCl₃) δ 8.78-8.76 (m, 1H), 8.64 (s, 1H), 8.21(d, 1H), 7.82 (dt, 1H), 7.38-7.35 (m, 1H), 7.32-7.21 (m, 2H), 7.09-7.04(m, 2H), 6.17 (s, 2H).

Example 10 Biological Activity Measurement by the sGC-HEK-cGMP Assay

Human embryonic kidney cells (HEK293), endogenously expressing solubleguanylate cyclase (sGC), were used to evaluate the activity of the testcompounds. Compounds stimulating the sGC receptor should cause anincrease in the intracellular concentration of cGMP. HEK 293 cells wereseeded in Dulbecco's Modification of Eagle's Medium supplemented withfetal bovine serum (10% final) and L-glutamine (2 mM final) in a 200 μLvolume at a density of 1×10⁵ cells/well in a poly-D-lysine coated 96well flat bottom plate and grown overnight at 37° C. Medium wasaspirated and cells were washed with 1× Hank's Buffered Saline SaltSolution (200 μL). Cells were then incubated for 15 minutes at 37° C.with 0.5 mM 3-isobutyl-1-methylxanthine (200 μL). Test article was thenadded to the assay mixture (2 μL) and incubated in the presence of 10 μMSodium Nitroprusside (SNP) at 37° C. for 10 minutes. After the 10 minuteincubation, the assay mixture was aspirated and 0.1M HCl (200 μL) wasadded to the cells. The plate was incubated at 4° C. for 30 minutes inthe 0.1M HCl to stop the reaction and lysed the cells. The plates werethen centrifuged at 1,200 g for 5 minutes at room temperature.Supernatants were collected and transferred to a new flat bottom 96 wellplate for analysis. Vehicle controls were carried out using DMSO (1%). Aknown sGC stimulator, BAY 41-2272, was used as the positive control.

Samples were diluted with an equal volume of 1 M Ammonium Acetate (pH 7)to neutralize samples for better chromatography. A 2×cGMP standard curvewas prepared in 0.1 M HCl and then diluted with an equal volume of 1 MAmmonium Acetate, with the following final concentrations in nM: 1024,512, 256, 128, 64, 32, 16, 8, 4, 2, 1.cGMP concentrations weredetermined from each sample using the LC/MS conditions (Table 2 below)and calculated standard curve. EC50 values were calculated fromconcentration-response curves generated with GraphPad Prism Software.

TABLE 2 (LC/MS experimental conditions) MS: Thermo Quantum or WatersLCMS Ion Mode: ESI⁺ Scan Type: MRM Dwell Collision Retention Time EnergyTube Time Compound: Transition (msec) (V) Lens (min) cGMP 346 >152 10028 139 1.0 HPLC: Agilent Technologies 1200 Series with CTC Analytics HTSPAL Column: Thermo Hypersil Gold 2.1 × 50 mm 5 micron particle size FlowRate: 403 uL/min Column RT Temperature: Autosampler 6° C. Temperature:Injection Volume: 20 uL Mobile Phases: A = 98:2 Water:Acetonitrile +0.1% Formic Acid B = 2:98 Water:Acetonitrile + 0.1% Formic AcidGradient: Time (min) % A % B 0 100 0 0.3 30 70 2.00 30 70 2.01 100 0 4100 0

The biological activities of some of the compounds according to FormulaIA or Formula IB determined with the sGC-HEK assay are summarized inTable 3 below.

TABLE 3 Test HEK Assay HEK Assay Compound (% E_(max) at 10 μm)* (%E_(max) at 30 μm)* I-1 B D I-2 B B I-3 A D I-4 D E I-5 B C I-6 D D I-7 AB I-8 A A I-9 A B I-11 C C I-12 D E I-13 A A I-14 B C I-16 A B I-18 A AI-19 C A I-20 A A I-21 A A I-24 B C I-25 D E I-26 C C I-27 A A I-28 A AI-29 A A I-30 C D I-31 A A I-32 A C I-35 A A I-36 A A I-37 C D I-38 E DI-39 B B I-40 D C I-41 E F I-42 A B I-43 A A I-44 E F I-45 A A I-46 D DI-47 A A I-48 E F I-49 A B I-50 D D I-51 D D I-52 A A I-53 E F I-54 D EI-55 A B I-56 C E I-57 A A I-58 E F I-59 A A I-60 C D I-61 D E I-62 C BI-63 F D I-64 C B I-65 G G I-66 E E I-67 C C I-68 D E *The compoundswere tested at a concentration of 10 or 30 μM. The code for the sGCactivity expressed as % E_(max) (i.e., percentage of the sGC activityobtained with the positive control, BAY 41-2272, of Bayer; whereinE_(max) = 100% was the sGC activity in the HEK assay obtained with thepositive control) obtained is: A = 0 to <5% B = 5 to <10% C = 10 to <20%D = 20 to <40% E = 40 to <60%

Example 11 Biological Activity Measurements by the Purified Human sGCEnzyme Activity Assay

Human soluble guanylate cyclase enzyme (hsGC) obtained from Enzo Inc.(P/N: ALX-201-177) was used to evaluate the activity of test compounds.The assay reactions contained 0.1 M Tris (pH 8.0), 0.5 mg/mL BSA (pH8.0), 2 mM DTT, 2 mM MgCl₂, 300 μM GTP, 1 mM 3-isobutyl-1-methylxanthine(IBMX) and 5 ng human soluble guanylate cyclase enzyme. Test compoundsin DMSO were then added (2 μL, 10 or 30 μM final concentration) andincubated (200 μL, 96-well plate format) at 37° C. for 30 minutes. Thecontrols were carried out using 2 μL DMSO. After the 30 minuteincubation, the reaction was stopped with the addition of 200 μL of coldmethanol. The plate was then centrifuged at 3,200 rpm for 10 minutes atroom temperature. Supernatants (200 μL) were collected and transferredto a new 96 well plate for analysis.

An 8 point cGMP (Sigma-Aldrich P/N: G6129) standard curve was preparedin assay buffer ranging from 0.156-20 Samples for the cGMP standardcurve were then diluted with an equal volume of methanol resulting infinal cGMP concentrations of 0.078-10 μM.

cGMP concentrations in all samples were determined using LC/MS/MSanalysis, using the conditions listed in Table 4 below. The cGMPstandard curve was generated using GraphPad Prism Software.

Calculations: Specific Activity was determined by the amount of cGMPformed (nmoles) per mg of sGC per min. Enzyme activity “fold-change” wascalculated by dividing the Specific Activity for a test compound by theSpecific Activity of DMSO control.

TABLE 4 LC/MS/MS method for detection of cGMP Inlet Method: HPLC: WatersAcquity Column: Thermo Hypersile Gold PFP, 2.1 × 30 mm, 3 μm GuardColumn: Thermo Hypersile Gold, 2.1 × 10 mm Column Temp: 25° C. FlowRate: 0.4 mL/min Auto sampler: Acquity; 6° C. Injection Volume: 10 uLMobile Phases: A = 0.1% Acetic Acid (v/v) in 100% water B = 0.1% AceticAcid (v/v) in 100 methanol Gradient: Time (min) % A % B Curve 0   95  56 0.5 95  5 6 0.6 10 90 6 2.0 10 90 6 2.1 95  5 6 4   (end) MS File:cGMP.exp Mass Spectrum: Waters Quattro micro Ionization: ES ⁺ Source,Desolvation: 150° C., 450° C. MS Function: MRM Collision Dwell ConeEnergy Compound Transition (sec) (V) (eV) cGMP 346 > 152 0.1 35 20

The enzymatic activity fold-change of the purified human sGC enzymedetermined in the presence of each of the test compounds individually at10 or 30 μm without the addition of sodium nitroprusside (SNP), a nitricoxide donor, is presented in Table 5.

Enzyme assays were also performed as described above, but in thepresence of 1 nM sodium nitroprusside (SNP). The results of the enzymeactivity assay performed in the presence of SNP are also presented inTable 5. Enzymatic activity fold-changes are reported for selected testcompounds in the presence of both SNP and the test compound. These werecalculated by dividing the specific activity (activity increase) for thetest compound dissolved in DMSO and SNP over the specific activity forthe mixture of DMSO and SNP.

TABLE 5 (Enzyme Data With or without SNP) sGC Enzyme sGC Enzyme sGCEnzyme sGC Enzyme Activity Activity Activity Activity Increase at 10Increase at 30 Increase at Increase at μM without μM without 10 μM 30 μMCompound SNP* SNP* with SNP* with SNP* I-1 B C B C I-2 N D N C I-3 N B ND I-4 N C N E I-5 N B N C I-6 N D N D I-7 N B N B I-8 N C N B I-9 N C NB I-11 N C N C I-12 N C N E I-13 N C N B I-14 N B N C I-16 N B N C I-18N B N C I-19 N B N C I-20 N B N B I-21 N B N B I-24 N C N C I-25 N D N EI-26 N C N D I-27 N B N B I-28 N B N B I-29 N B N C I-30 N B N C I-31 NB N C I-32 N C N C I-35 N B N C I-36 N B N B I-37 N C N D I-38 N C N EI-39 N B N C I-40 N B N D I-41 N C N E I-42 N B N C I-43 N B N B I-44 ND N F I-45 N B N B I-46 N B N C I-47 N B N B I-48 N C N D I-49 N B N BI-50 N B N C I-51 N C N E I-52 N B N B I-53 N D N F I-54 N C N D I-55 NB N C I-56 N B N D I-57 N B N C I-58 N C N D I-59 N A N A I-60 N B N DI-61 N C N D I-62 N A N C I-63 N B N D I-65 N D N E I-68 N C N E *Codefor the increase in the activity of the sGC enzyme in the presence ofthe test compound with or without SNP: A = no increase to <1 foldincrease B = 1 to <2 fold increase C = 2 to <5 fold increase D = 5 to<10 fold increase E = 10 to <20 fold increase F = 20 to <50 foldincrease N = not determined

Example 12 Biological Activity Measurement by the Thoracic Aortic RingsAssay

Thoracic aortic rings were dissected from anesthetized (isoflurane) maleSprague-Dawley rats weighing 275-299 g. Tissues were immediatelytransferred to ice-cold Krebs-Henseleit solution, which had been aeratedwith 95% O₂ and 5% CO₂ for 30 minutes.

Following removal of connective tissue, aortic sections were cut into 4rings (˜2 mm each) and suspended on 2 L-shaped hooks, with one hookfixed at the bottom of the tissue bath (Schuler Organ Bath, HarvardApparatus) and the other connected to a force transducer (F30 ForceTransducer, Harvard Apparatus). Baths contained Krebs Henseleit solution(10 mL) heated to 37° C. and aerated with 95% O₂ and 5% CO₂. Rings werebrought to an initial tension of 0.3-0.5 g and gradually raised to aresting tension of 1.0 g over 60 minutes. Rings were rinsed with KrebsHenseleit solution (heated to 37° C. and aerated with 95% O₂ and 5% CO₂)at 15 minute intervals until a stable baseline was obtained. Rings wereconsidered to be stable after a resting tension of 1.0 g was maintained(for approximately 10 minutes) without need for adjustment. Rings werethen contracted with 100 ng/mL phenylephrine by adding 100 μL of a 10μg/mL phenylephrine stock solution. Tissues achieving a stablecontraction were then treated in a cumulative, dose dependent mannerwith test compounds prepared in dimethylsulfoxide (DMSO). In some cases,tissues were rinsed three times over a 5 minute period withKrebs-Heinseleit's solution (heated to 37° C. and aerated with 95% O₂and 5% CO₂), allowed to stabilize at baseline, and then used forcharacterization of other test articles or DMSO effects. All data werecollected using the HSE-ACAD software provided by Harvard Apparatus.Percent relaxation effects were calculated in Microsoft Excel using therecorded tension value of 100 ng/mL phenylephrine treatment as 0%inhibition and, after washing the tissue with buffer, the originalresting tension of tissue is used as 100% inhibition. EC₅₀ values werecalculated from concentration-response curves generated with GraphPadPrism Software.

The biological data for some of the compounds of Formula IA and FormulaIB, in comparison with the prior art compound, BAY 41-2272, as thereference compound, determined by the thoracic aorta ring assay arepresented in Table 6 below.

TABLE 6 Thoracic Ring Assay Results* Percent Percent Percent CompoundRelaxation Relaxation Relaxation Aortic Ring Tested at 1 μM* at 3 μM* at10 μM* EC₅₀ (μM)** BAY-41-2272 N N N A I-1 C E G B I-3 D F G B I-4 E G NA I-6 C E G B I-12 D F G A I-25 D F G A I-30 C E G C I-38 D F G B I-40 CE G B I-41 F G G A I-44 F G G A I-46 C E F C I-48 D F G B I-50 B C E NI-53 C F G B I-61 E F N A *Each of the compound was tested at aconcentration of 1, 3 or 10 μM to obtain data using the method describedin Example 11. The code for the percent relaxation of the aotic ring is:A = 0 to <10% B = 10 to <20% C = 20 to <40% D = 40 to <60% E = 60 to<80% F = 80 to <100% G = 100 to <120% N = not determined **The code forthe EC₅₀ value obtained is: A = 0 to <1 μM B = 1 to <2 μM C = 2 to <3 μMN = not determined

A number of embodiments have been described. Nevertheless, it will beunderstood that various modifications may be made without departing fromthe spirit and scope of the invention.

We claim: 1-82. (canceled)
 83. A method of treating a disease, healthcondition or disorder in a subject, comprising administering atherapeutically effective amount of a compound of Formula IA or FormulaIB, or a pharmaceutically acceptable salt thereof, to the subject inneed of the treatment, wherein the disease, health condition or disorderis (a) a peripheral or cardiac vascular disorder or health conditionselected from: pulmonary hypertension, pulmonary arterial hypertension,and associated pulmonary vascular remodeling, localized pulmonarythrombosis, right heart hypertrophy, pulmonary hypertonia, primarypulmonary hypertension, secondary pulmonary hypertension, familialpulmonary hypertension, sporadic pulmonary hypertension, pre-capillarypulmonary hypertension, idiopathic pulmonary hypertension, thromboticpulmonary artheriopathy, plexogenic pulmonary artheriopathy; pulmonaryhypertension associated with or related to: left ventriculardysfunction, hypoxemia, mitral valve disease, constrictive pericarditis,aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonaryfibrosis, anomalous pulmonary venous drainage, pulmonary venooclusivedisease, pulmonary vasculitis, collagen vascular disease, congenitalheart disease, pulmonary venous hypertension, interstitial lung disease,sleep-disordered breathing, apnea, alveolar hypoventilation disorders,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorders, chronic thromboembolism, pulmonary embolism, connectivetissue disease, lupus, schitosomiasis, sarcoidosis, chronic obstructivepulmonary disease, emphysema, chronic bronchitis, pulmonary capillaryhemangiomatosis; histiocytosis X, lymphangiomatosis and compressedpulmonary vessels; (b) a health disorder related to high blood pressureand decreased coronary blood flow selected from: increased acute andchronic coronary blood pressure, arterial hypertension, vasculardisorder resulting from heart disease, stroke, cerebral ischemia, orrenal failure, congestive heart failure, thromboembolic disorders,ischemias, myocardial infarction, stroke, transient ischemic attacks,stable or unstable angina pectoris, arrhythmias, diastolic dysfunction,coronary insufficiency; (c) atherosclerosis, restenosis, percutaneoustransluminal coronary angioplasties or inflammation; (d) livercirrhosis, hepatic fibrosis, hepatic stellate cell activation, hepaticfibrous collagen and total collagen accumulation, liver disease ofnecro-inflammatory and/or of immunological origin; or (e) a urogenitalsystem disorder selected from renal fibrosis, renal failure resultingfrom chronic kidney diseases or insufficiency, prostate hypertrophy,erectile dysfunction, female sexual dysfunction and incontinence;wherein the compound of Formula IA or Formula IB is:

the symbol with the encircled letter B represents ring B, and ring B isa phenyl or a 6-membered heteroaryl ring, having 1 or 2 nitrogen ringatoms; n is an integer selected from 0 to 3; each J^(B) is independentlyselected from halogen, —CN, —NO₂, a C₁₋₆ aliphatic, —OR^(B) or a C₃₋₈cycloaliphatic group; wherein each said C₁₋₆ aliphatic and each saidC₃₋₈ cycloaliphatic group is optionally and independently substitutedwith up to 3 instances of R³; each R^(B) is independently selected fromhydrogen, a C₁₋₆ aliphatic or a C₃₋₈ cycloaliphatic; wherein each saidC₁₋₆ aliphatic and each said C₃₋₈ cycloaliphatic ring is optionally andindependently substituted with up to 3 instances of R³; each R³ isindependently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); wherein ring D is the 5-memberedring heteroaryl of Formula IB or the 6-membered heteroaryl ring ofFormula IA that is substituted by m instances of J^(D); X is selectedfrom N or C; each Y is independently selected from C, N, O or S; whereina minimum of 0 and maximum of 3 instances of Y can be N, O or Ssimultaneously and the remaining instance or instances of Y are C; m isan integer selected from 0 to 3; each J^(D) that is a substituent on acarbon ring atom of Formula IA or Formula IB is independently selectedfrom halogen, —NO₂, —OR^(D), —SR^(D), —C(O)R^(D), —C(O)OR^(D),—C(O)N(R^(D))₂, —CN, —N(R^(D))₂, —N(R^(d))C(O)R^(D),—N(R^(d))C(O)OR^(D), —SO₂R^(D), —SO₂N(R^(D))₂, —N(R^(d))SO₂R^(D), a C₁₋₆aliphatic, —(C₁₋₆ aliphatic)-R^(D), a C₃₋₈ cycloaliphatic ring, a 6 to10-membered aryl ring, a 4 to 8-membered heterocyclic ring or a 5 to10-membered heteroaryl ring; wherein each said 4 to 8-memberedheterocylic ring and each said 5 to 10-membered heteroaryl ring containsbetween 1 and 3 heteroatoms independently selected from O, N or S; andwherein each said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring,each said 6 to 10-membered aryl ring, each said 4 to 8-memberedheterocyclic ring and each said 5 to 10-membered heteroaryl ring isoptionally and independently substituted with up to 3 instances of R⁵;each J^(D) that is a substituent on a nitrogen ring atom of Formula IBis independently selected from —C(O)R^(D), —C(O)OR^(D), —C(O)N(R^(D))₂,—SO₂R^(D), —SO₂N(R^(D))₂, a C₁₋₆ aliphatic, —(C₁₋₆ aliphatic)-R^(D), aC₃₋₈ cycloaliphatic ring, a 6 to 10-membered aryl ring, a 4 to8-membered heterocyclic ring or a 5 to 10-membered heteroaryl ring;wherein each said 4 to 8-membered heterocylic ring and each said 5 to10-membered heteroaryl ring has between 1 and 3 heteroatomsindependently selected from O, N or S; and wherein each said C₁₋₆aliphatic, each said C₃₋₈ cycloaliphatic ring, each said 6 to10-membered aryl ring, each said 4 to 8-membered heterocyclic ring andeach said 5 to 10-membered heteroaryl ring is optionally andindependently substituted with up to 3 instances of R⁵; each R^(D) isindependently selected from hydrogen, a C₁₋₆ aliphatic, —(C₁₋₆aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4 to 8-memberedheterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; whereineach said 4 to 8-membered heterocylic ring and each said 5 to 6-memberedheteroaryl ring has between 1 and 3 heteroatoms independently selectedfrom O, N or S; and wherein each said C₁₋₆ aliphatic, each said C₃₋₈cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring, eachsaid phenyl and each said 5 to 6-membered heteroaryl ring is optionallyand independently substituted with up to 3 instances of R⁵; each R^(d)is independently selected from hydrogen, a C₁₋₆ aliphatic, —(C₁₋₆aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4 to 8-memberedheterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; whereineach said heterocylic ring and each said heteroaryl ring has between 1and 3 heteroatoms independently selected from O, N or S; and whereineach said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring, each said4 to 8-membered heterocyclic ring, each said phenyl and each said 5 to6-membered heteroaryl ring is optionally and independently substitutedby up to 3 instances of R⁵; each R^(f) is independently selected from aC₃₋₈ cycloaliphatic ring, a 4 to 8-membered heterocyclic ring, phenyl ora 5 to 6-membered heteroaryl ring; wherein each said heterocylic ringand each said heteroaryl ring has between 1 and 3 heteroatomsindependently selected from O, N or S; and wherein each said C₁₋₆aliphatic, each said C₃₋₈ cycloaliphatic ring, each said 4 to 8-memberedheterocyclic ring, each said phenyl and each said 5 to 6-memberedheteroaryl ring is optionally and independently substituted by up to 3instances of R⁵; alternatively, two instances of R^(D) linked to thesame nitrogen atom of J^(D), together with said nitrogen atom of J^(D),form a 4 to 8-membered heterocyclic ring or a 5-membered heteroarylring; wherein each said 4 to 8-membered heterocyclic ring and each said5-membered heteroaryl ring optionally has up to 2 additional heteroatomsindependently selected from N, O or S, and wherein each said 4 to8-membered heterocyclic ring and each said 5-membered heteroaryl ring isoptionally and independently substituted by up to 3 instances of R⁵; oralternatively, one instance of R^(D) linked to a carbon, oxygen orsulfur atom of J^(D) and one instance of R^(d) linked to a nitrogen atomof the same J^(D), together with said carbon, oxygen or sulfur and saidnitrogen atom of that same J^(D), form a 4 to 8-membered heterocyclicring or a 5-membered heteroaryl ring; wherein each said 4 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring optionallyhas up to 2 additional heteroatoms independently selected from N, O orS, and wherein each said 4 to 8-membered heterocyclic ring and each said5-membered heteroaryl ring is optionally and independently substitutedby up to 3 instances of R⁵; each R⁵ is independently selected fromhalogen, —CN, —NO₂, C₁₋₄ alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, —OR⁶, —SR⁶, —COR⁶, —C(O)OR⁶,—C(O)N(R⁶)₂, N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶,phenyl or an oxo group; wherein each said phenyl group is optionally andindependently substituted with up to 3 instances of halogen, —OH, —NH₂,—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and wherein each said C₇₋₁₂aralkyl and each said cycloalkyl group is optionally and independentlysubstituted with up to 3 instances of halogen; each R⁶ is independentlyselected from hydrogen, a C₁₋₄ alkyl, phenyl, a C₇₋₁₂ aralkyl or a C₃₋₈cycloalkyl ring; wherein each of said C₁₋₄ alkyl, each said phenyl, eachsaid C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally andindependently substituted with up to 3 instances of halogen;alternatively, two instances of R⁶ linked to the same nitrogen atom ofR⁵, together with said nitrogen atom of R⁵, form a 5 to 8-memberedheterocyclic ring or a 5-membered heteroaryl ring; wherein each said 5to 8-membered heterocyclic ring and each said 5-membered heteroaryl ringoptionally has up to 2 additional heteroatoms independently selectedfrom N, O or S; or alternatively, one instance of R⁶ linked to anitrogen atom of R⁵ and one instance of R⁶ linked to a carbon or sulfuratom of the same R⁵, together with said nitrogen and said carbon orsulfur atom of the same R⁵, form a 5 to 8-membered heterocyclic ring ora 5-membered heteroaryl ring; wherein each said 5 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring optionallyhas up to 2 additional heteroatoms independently selected from N, O orS; or, alternatively, two J^(D) groups attached to two vicinal ring Datoms, taken together with said two vicinal ring D atoms, form a 5 to7-membered heterocycle resulting in a fused ring D wherein said 5 to7-membered heterocycle has from 1 to 3 heteroatoms independentlyselected from N, O or S; and wherein said 5 to 7-membered heterocycle isoptionally and independently substituted by up to 3 instances ofhalogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, —O(Cl₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; R^(C) isselected from halo, —CN, C₁₋₆ alkyl or a ring C; ring C is a phenylring, a monocyclic 5 or 6-membered heteroaryl ring, a bicyclic 8 to10-membered heteroaryl ring, a monocyclic 3 to 10-memberedcycloaliphatic ring, or a monocyclic 4 to 10-membered heterocycle;wherein said monocyclic 5 or 6-membered heteroaryl ring, said bicyclic 8to 10-membered heteroaryl ring, or said monocyclic 4 to 10-memberedheterocycle has between 1 and 4 heteroatoms selected from N, O or S; andwherein said phenyl, monocyclic 5 to 6-membered heteroaryl ring,bicyclic 8 to 10-membered heteroaryl ring, or monocyclic 4 to10-membered heterocycle is optionally and independently substituted withup to 3 instances of J^(C); each J^(C) is independently selected fromhalogen, —CN, —NO₂, a C₁₋₆ aliphatic, —OR^(H), —SR^(H), —N(R^(H))₂, aC₃₋₈ cycloaliphatic ring or a 4 to 8-membered heterocyclic ring; whereinsaid 4 to 8-membered heterocyclic ring has 1 or 2 heteroatomsindependently selected from N, O or S; wherein each said C₁₋₆ aliphatic,each said C₃₋₈ cycloaliphatic ring and each said 4 to 8-memberedheterocyclic ring, is optionally and independently substituted with upto 3 instances of R⁷; or alternatively, two J^(C) groups attached to twovicinal ring C atoms, taken together with said two vicinal ring C atoms,form a 5 to 7-membered heterocycle resulting in a fused ring C; whereinsaid 5 to 7-membered heterocycle has from 1 to 2 heteroatomsindependently selected from N, O or S; each R^(H) is independentlyselected from hydrogen, a C₁₋₆ aliphatic, a C₃₋₈ cycloaliphatic ring ora 4 to 8-membered heterocyclic ring; wherein each said 4 to 8-memberedheterocylic ring has between 1 and 3 heteroatoms independently selectedfrom O, N or S; and wherein each said C₁₋₆ aliphatic, each said C₃₋₈cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring, isoptionally and independently substituted with up to 3 instances of R⁷;alternatively, two instances of R^(H) linked to the same nitrogen atomof J^(C), together with said nitrogen atom of J^(C), form a 4 to8-membered heterocyclic ring or a 5-membered heteroaryl ring; whereineach said 4 to 8-membered heterocyclic ring and each said 5-memberedheteroaryl ring optionally has up to 2 additional heteroatomsindependently selected from N, O or S, and wherein each said 4 to8-membered heterocyclic ring and each said 5-membered heteroaryl ring isoptionally and independently substituted by up to 3 instances of R⁷; oreach R⁷ is independently selected from halogen, —CN, —NO₂, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —SR⁸, —N(R⁸)₂, or an oxogroup; wherein each said cycloalkyl group is optionally andindependently substituted with up to 3 instances of halogen; each R⁸ isindependently selected from hydrogen, a C₁₋₄ alkyl, C₁₋₄ haloalkyl or aC₃₋₈ cycloalkyl ring; wherein each said cycloalkyl group is optionallyand independently substituted with up to 3 instances of halogen; andalternatively, two instances of R⁸ linked to the same nitrogen atom ofR⁷, together with said nitrogen atom of R⁷, form a 5 to 8-memberedheterocyclic ring or a 5-membered heteroaryl ring; wherein each said 5to 8-membered heterocyclic ring and each said 5-membered heteroaryl ringoptionally has up to 2 additional heteroatoms independently selectedfrom N, O or S.
 84. The method of claim 83, wherein the disease, healthcondition or disorder is (a) a peripheral or cardiac vascular disorderor health condition selected from: pulmonary hypertension, pulmonaryarterial hypertension, and associated pulmonary vascular remodeling,localized pulmonary thrombosis, right heart hypertrophy, pulmonaryhypertonia, primary pulmonary hypertension, secondary pulmonaryhypertension, familial pulmonary hypertension, sporadic pulmonaryhypertension, pre-capillary pulmonary hypertension, idiopathic pulmonaryhypertension, thrombotic pulmonary artheriopathy, plexogenic pulmonaryartheriopathy; pulmonary hypertension associated with or related to:left ventricular dysfunction, hypoxemia, mitral valve disease,constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinalfibrosis, pulmonary fibrosis, anomalous pulmonary venous drainage,pulmonary venooclusive disease, pulmonary vasculitis, collagen vasculardisease, congenital heart disease, pulmonary venous hypertension,interstitial lung disease, sleep-disordered breathing, apnea, alveolarhypoventilation disorders, chronic exposure to high altitude, neonatallung disease, alveolar-capillary dysplasia, sickle cell disease, othercoagulation disorders, chronic thromboembolism, pulmonary embolism,connective tissue disease, lupus, schitosomiasis, sarcoidosis, chronicobstructive pulmonary disease, emphysema, chronic bronchitis, pulmonarycapillary hemangiomatosis; histiocytosis X, lymphangiomatosis orcompressed pulmonary vessels; (b) liver cirrhosis, or (c) a urogenitalsystem disorder selected from renal fibrosis, renal failure resultingfrom chronic kidney diseases or insufficiency, erectile dysfunction orfemale sexual dysfunction.
 85. The method of claim 84, wherein thedisease, health condition or disorder is pulmonary hypertension,pulmonary arterial hypertension, and associated pulmonary vascularremodeling, localized pulmonary thrombosis, right heart hypertrophy,pulmonary hypertonia, primary pulmonary hypertension, secondarypulmonary hypertension, familial pulmonary hypertension, sporadicpulmonary hypertension, pre-capillary pulmonary hypertension, idiopathicpulmonary hypertension, thrombotic pulmonary arteriopathy, plexogenicpulmonary arteriopathy or chronic obstructive pulmonary disease, livercirrhosis, renal fibrosis, renal failure resulting from chronic kidneydiseases or insufficiency, erectile dysfunction or female sexualdysfunction.
 86. The method of claim 85, wherein the disease, healthcondition or disorder is pulmonary hypertension, pulmonary arterialhypertension, and associated pulmonary vascular remodeling, pulmonaryhypertonia, primary pulmonary hypertension, secondary pulmonaryhypertension, familial pulmonary hypertension, sporadic pulmonaryhypertension, pre-capillary pulmonary hypertension or idiopathicpulmonary hypertension.
 87. The method of claim 83, further comprisingadministering an effective amount of one or more additional therapeuticagents to the subject.
 88. The method of claim 87, wherein the one ormore additional therapeutic agents are selected from edothelium-derivedreleasing factor, NO donors, substances that enhance cGMPconcentrations, nitric oxide synthase substrates, compounds whichenhance eNOS transcription, NO-independent heme-independent sGCactivators, heme-dependent sGC stimulators; inhibitors of cGMPdegradation, calcium channel blockers, endothelin receptor antagonists,prostacyclin derivatives, antihyperlipidemics, anticoagulants,antiplatelet drugs, ACE inhibitors, supplemental oxygen, beta blockers,antiarrhythmic agents, diuretics, exogenous vasodilators,bronchodilators, corticosteroids, dietary supplements, PGD2 receptorantagonists, immunosuppressants, non-steroidal antiasthmatics,non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors oranti-diabetic agents.
 89. (canceled)
 90. The method of claim 85, furthercomprising administering an effective amount of one or more additionaltherapeutic agents to the subject.
 91. The method of claim 90, whereinthe one or more additional therapeutic agents are selected fromedothelium-derived releasing factor, NO donors, substances that enhancecGMP concentrations, nitric oxide synthase substrates, compounds whichenhance eNOS transcription, NO-independent heme-independent sGCactivators, heme-dependent sGC stimulators; inhibitors of cGMPdegradation, calcium channel blockers, endothelin receptor antagonists,prostacyclin derivatives, antihyperlipidemics, anticoagulants,antiplatelet drugs, ACE inhibitors, supplemental oxygen, beta blockers,antiarrhythmic agents, diuretics, exogenous vasodilators,bronchodilators, corticosteroids, dietary supplements, PGD2 receptorantagonists, immunosuppressants, non-steroidal antiasthmatics,non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors oranti-diabetic agents.
 92. The method of claim 86, further comprisingadministering an effective amount of one or more additional therapeuticagents to the subject.
 93. The method of claim 92, wherein the one ormore additional therapeutic agents are selected from edothelium-derivedreleasing factor, NO donors, substances that enhance cGMPconcentrations, nitric oxide synthase substrates, compounds whichenhance eNOS transcription, NO-independent heme-independent sGCactivators, heme-dependent sGC stimulators; inhibitors of cGMPdegradation, calcium channel blockers, endothelin receptor antagonists,prostacyclin derivatives, antihyperlipidemics, anticoagulants,antiplatelet drugs, ACE inhibitors, supplemental oxygen, beta blockers,antiarrhythmic agents, diuretics, exogenous vasodilators,bronchodilators, corticosteroids, dietary supplements, PGD2 receptorantagonists, immunosuppressants, non-steroidal antiasthmatics,non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors oranti-diabetic agents.
 94. A method of treating a disease, healthcondition or disorder in a subject, comprising administering atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable salt thereof, selected from:

to the subject in need of the treatment, wherein the disease, healthcondition or disorder is (a) a peripheral or cardiac vascular disorderor health condition selected from: pulmonary hypertension, pulmonaryarterial hypertension, and associated pulmonary vascular remodeling,localized pulmonary thrombosis, right heart hypertrophy, pulmonaryhypertonia, primary pulmonary hypertension, secondary pulmonaryhypertension, familial pulmonary hypertension, sporadic pulmonaryhypertension, pre-capillary pulmonary hypertension, idiopathic pulmonaryhypertension, thrombotic pulmonary artheriopathy, plexogenic pulmonaryartheriopathy; pulmonary hypertension associated with or related to:left ventricular dysfunction, hypoxemia, mitral valve disease,constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinalfibrosis, pulmonary fibrosis, anomalous pulmonary venous drainage,pulmonary venooclusive disease, pulmonary vasculitis, collagen vasculardisease, congenital heart disease, pulmonary venous hypertension,interstitial lung disease, sleep-disordered breathing, apnea, alveolarhypoventilation disorders, chronic exposure to high altitude, neonatallung disease, alveolar-capillary dysplasia, sickle cell disease, othercoagulation disorders, chronic thromboembolism, pulmonary embolism,connective tissue disease, lupus, schitosomiasis, sarcoidosis, chronicobstructive pulmonary disease, emphysema, chronic bronchitis, pulmonarycapillary hemangiomatosis; histiocytosis X, lymphangiomatosis andcompressed pulmonary vessels; (b) a health disorder related to highblood pressure and decreased coronary blood flow selected from:increased acute and chronic coronary blood pressure, arterialhypertension, vascular disorder resulting from heart disease, stroke,cerebral ischemia, or renal failure, congestive heart failure,thromboembolic disorders, ischemias, myocardial infarction, stroke,transient ischemic attacks, stable or unstable angina pectoris,arrhythmias, diastolic dysfunction, coronary insufficiency; (c)atherosclerosis, restenosis, percutaneous transluminal coronaryangioplasties or inflammation; (d) liver cirrhosis, hepatic fibrosis,hepatic stellate cell activation, hepatic fibrous collagen and totalcollagen accumulation, liver disease of necro-inflammatory and/or ofimmunological origin; or (e) a urogenital system disorder selected fromrenal fibrosis, renal failure resulting from chronic kidney diseases orinsufficiency, prostate hypertrophy, erectile dysfunction, female sexualdysfunction and incontinence.
 95. The method of claim 94, wherein thedisease, health condition or disorder is (a) a peripheral or cardiacvascular disorder or health condition selected from: pulmonaryhypertension, pulmonary arterial hypertension, and associated pulmonaryvascular remodeling, localized pulmonary thrombosis, right hearthypertrophy, pulmonary hypertonia, primary pulmonary hypertension,secondary pulmonary hypertension, familial pulmonary hypertension,sporadic pulmonary hypertension, pre-capillary pulmonary hypertension,idiopathic pulmonary hypertension, thrombotic pulmonary artheriopathy,plexogenic pulmonary artheriopathy; pulmonary hypertension associatedwith or related to: left ventricular dysfunction, hypoxemia, mitralvalve disease, constrictive pericarditis, aortic stenosis,cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalouspulmonary venous drainage, pulmonary venooclusive disease, pulmonaryvasculitis, collagen vascular disease, congenital heart disease,pulmonary venous hypertension, interstitial lung disease,sleep-disordered breathing, apnea, alveolar hypoventilation disorders,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorders, chronic thromboembolism, pulmonary embolism, connectivetissue disease, lupus, schitosomiasis, sarcoidosis, chronic obstructivepulmonary disease, emphysema, chronic bronchitis, pulmonary capillaryhemangiomatosis; histiocytosis X, lymphangiomatosis or compressedpulmonary vessels; (b) liver cirrhosis, or (c) a urogenital systemdisorder selected from renal fibrosis, renal failure resulting fromchronic kidney diseases or insufficiency, erectile dysfunction or femalesexual dysfunction.
 96. The method of claim 95, wherein the disease,health condition or disorder is pulmonary hypertension, pulmonaryarterial hypertension, and associated pulmonary vascular remodeling,localized pulmonary thrombosis, right heart hypertrophy, pulmonaryhypertonia, primary pulmonary hypertension, secondary pulmonaryhypertension, familial pulmonary hypertension, sporadic pulmonaryhypertension, pre-capillary pulmonary hypertension, idiopathic pulmonaryhypertension, thrombotic pulmonary arteriopathy, plexogenic pulmonaryarteriopathy or chronic obstructive pulmonary disease, liver cirrhosis,renal fibrosis, renal failure resulting from chronic kidney diseases orinsufficiency, erectile dysfunction or female sexual dysfunction. 97.The method of claim 96, wherein the disease, health condition ordisorder is pulmonary hypertension, pulmonary arterial hypertension, andassociated pulmonary vascular remodeling, pulmonary hypertonia, primarypulmonary hypertension, secondary pulmonary hypertension, familialpulmonary hypertension, sporadic pulmonary hypertension, pre-capillarypulmonary hypertension or idiopathic pulmonary hypertension.
 98. Themethod of claim 95, further comprising administering an effective amountof one or more additional therapeutic agents to the subject.
 99. Themethod of claim 98, wherein the one or more additional therapeuticagents are selected from edothelium-derived releasing factor, NO donors,substances that enhance cGMP concentrations, nitric oxide synthasesubstrates, compounds which enhance eNOS transcription, NO-independentheme-independent sGC activators, heme-dependent sGC stimulators;inhibitors of cGMP degradation, calcium channel blockers, endothelinreceptor antagonists, prostacyclin derivatives, antihyperlipidemics,anticoagulants, antiplatelet drugs, ACE inhibitors, supplemental oxygen,beta blockers, antiarrhythmic agents, diuretics, exogenous vasodilators,bronchodilators, corticosteroids, dietary supplements, PGD2 receptorantagonists, immunosuppressants, non-steroidal antiasthmatics,non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors oranti-diabetic agents.
 100. The method of claim 96, further comprisingadministering an effective amount of one or more additional therapeuticagents to the subject.
 101. The method of claim 100, wherein the one ormore additional therapeutic agents are selected from edothelium-derivedreleasing factor, NO donors, substances that enhance cGMPconcentrations, nitric oxide synthase substrates, compounds whichenhance eNOS transcription, NO-independent heme-independent sGCactivators, heme-dependent sGC stimulators; inhibitors of cGMPdegradation, calcium channel blockers, endothelin receptor antagonists,prostacyclin derivatives, antihyperlipidemics, anticoagulants,antiplatelet drugs, ACE inhibitors, supplemental oxygen, beta blockers,antiarrhythmic agents, diuretics, exogenous vasodilators,bronchodilators, corticosteroids, dietary supplements, PGD2 receptorantagonists, immunosuppressants, non-steroidal antiasthmatics,non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors oranti-diabetic agents.
 102. The method of claim 97, further comprisingadministering an effective amount of one or more additional therapeuticagents to the subject.
 103. The method of claim 102, wherein the one ormore additional therapeutic agents are selected from edothelium-derivedreleasing factor, NO donors, substances that enhance cGMPconcentrations, nitric oxide synthase substrates, compounds whichenhance eNOS transcription, NO-independent heme-independent sGCactivators, heme-dependent sGC stimulators; inhibitors of cGMPdegradation, calcium channel blockers, endothelin receptor antagonists,prostacyclin derivatives, antihyperlipidemics, anticoagulants,antiplatelet drugs, ACE inhibitors, supplemental oxygen, beta blockers,antiarrhythmic agents, diuretics, exogenous vasodilators,bronchodilators, corticosteroids, dietary supplements, PGD2 receptorantagonists, immunosuppressants, non-steroidal antiasthmatics,non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors oranti-diabetic agents.